p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")
Other endogenous ligands that impact on the activity of nAChRs noncompetitively and voltage independently include the amyloid beta peptide 1-42 (Abeta1-42; Refs. 123, 376) and the canabinoid anandamide (356, 442). PubMed:19126755
It is noteworthy that the alpha7 nAChR activity increases intracellular accumulation of Abeta in neurons (336), and Abeta peptides, in addition to modulating nAChR activity, downregulate the expression of nAChRs (197). PubMed:19126755
Of note is that in both of these catastrophic disorders, reduced nAChR activity/expression is accompanied by increased levels of kynurenic acid (KYNA), a tryptophan metabolite that in the brain is primarily produced and released by astrocytes (244, 419). PubMed:19126755
Thus inhibitors of proteasome function block endoplasmic reticulum-associated degradation of unassembled AChR subunits, which in turn increases the availability of subunits for assembly into mature receptors that are trafficked to the cell surface. PubMed:19126755
Acetylcholine receptors (AChRs), like many other ligand-activated neurotransmitter receptors, consist of two major subtypes: the metabotropic muscarinic receptors and the ionotropic nicotinic receptors. Both share the property of being activated by the endogenous neurotransmitter acetylcholine (ACh), and they are expressed by both neuronal and nonneuronal cells throughout the body (8, 113, 142, 184). PubMed:19126755
Strain-dependent variations in nAChR density in regions of the rat brain have also been reported. PubMed:19126755
Other endogenous ligands that impact on the activity of nAChRs noncompetitively and voltage independently include the amyloid beta peptide 1-42 (Abeta1-42; Refs. 123, 376) and the canabinoid anandamide (356, 442). PubMed:19126755
Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443). PubMed:19126755
For instance, studies carried out in PC12 cells demonstrated that codeine, a drug with no significant effect on ChE, can activate nicotinic single-channel currents and that this nicotinic agonist effect is sensitive to inhibition by FK1 while unaffected by classical nAChR antagonists (450). PubMed:19126755
An alternative means to increase nicotinic functions in the brain is to sensitize the nAChRs to activation by the endogenous agonist(s) using the so-called nicotinic allosteric potentiating ligands (APLs), which include drugs such as physostigmine and galantamine, a drug currently approved for the treatment of AD. PubMed:19126755
In the early 1990s, galantamine, an alkaloid originally extracted from the bulbs and flowers of the wild Caucasian snowdrop Galanthus nivalis and other related Amaryllidacea species, was found to act like physostigmine on muscle and neuronal nAChRs (370, 372). PubMed:19126755
Surprisingly, however, activation of nAChRs by galantamine or physostigmine was insensitive to blockade by competitive nAChR antagonists, was detected even when the receptors were desensitized by high agonist concentrations, and was inhibited by the monoclonal antibody FK1 (350, 370, 372, 413, 428, 429). PubMed:19126755
The nicotinic APL action of galantamine appears to be an important determinant of its clinical effectiveness (reviewed in Refs. 98, 291, 371). Acting primarily as a nicotinic APL, galantamine improves synaptic transmission and decreases neurodegeneration, two effects essential for its cognitive-enhancing properties (40, 108, 241, 409, 521). PubMed:19126755
The other subtype of AChR is the fast ionotropic cationic nicotinic receptor channel (nAChR). These receptors are sensitive to activation by nicotine and have ion channels whose activity is induced in the micro- to submicrosecond range. PubMed:19126755
Also, the continuous exposure of cells to nicotine increases nAChR surface expression by reducing degradation of the intracellular pool of receptors (367, 394). PubMed:19126755
In the smoker’s brain, upregulation can increase high-affinity nicotine binding by nearly fourfold relative to age- and gender-matched controls that have not been exposed to nicotine (373, 421). The mechanism by which nicotine increases the total number of high-affinity nAChRs, though poorly defined, is highly conserved among species. PubMed:19126755
Mechanistically, nicotine, acting through nAChRs, decreases keratinocyte migration (188, 189) and modifies the activity of PI3K/Akt, ERK, MEK, and JAK signaling pathways. PubMed:19126755
First, age-related nAChR subunit expression decline was observed in both strains, and this was dominated by diminished alpha4 nAChR expression. Second, long-term (12 mo) oral nicotine failed to reduce the age-related decline in the number of neurons expressing alpha4 nAChR subunits, although the neurons that remained exhibited larger processes with more varicosities than age-matched controls (165, 396). Acute nicotine treatment (alpha6 wk of oral nicotine) of aged mice had no measurable influence on nAChR expression, neuronal viability, or dendritic complexity (e.g., Ref. 396) PubMed:19126755
Nicotine is perhaps the most addictive drug that is widely used; 95% or more of its users with a strong desire to stop using it relapse within 1 yr (47, 203). Chronic nicotine use and the phenotypes of addiction are closely associated in humans and other animals with concurrent physiological changes in nAChR function and expression PubMed:19126755
Nicotine is perhaps the most addictive drug that is widely used; 95% or more of its users with a strong desire to stop using it relapse within 1 yr (47, 203). Chronic nicotine use and the phenotypes of addiction are closely associated in humans and other animals with concurrent physiological changes in nAChR function and expression PubMed:19126755
An alternative means to increase nicotinic functions in the brain is to sensitize the nAChRs to activation by the endogenous agonist(s) using the so-called nicotinic allosteric potentiating ligands (APLs), which include drugs such as physostigmine and galantamine, a drug currently approved for the treatment of AD. PubMed:19126755
Studies from the early 1980s provided evidence that the cholinesterase (ChE) inhibitor physostigmine could interact directly with nAChRs at the frog neuromuscular junction and induce nicotinic single-channel currents (428, 429). PubMed:19126755
Surprisingly, however, activation of nAChRs by galantamine or physostigmine was insensitive to blockade by competitive nAChR antagonists, was detected even when the receptors were desensitized by high agonist concentrations, and was inhibited by the monoclonal antibody FK1 (350, 370, 372, 413, 428, 429). PubMed:19126755
The second was the discovery of alpha-bungarotoxin (alpha-BGT), a component of krait snake venom that binds muscle-type nAChRs with near covalent affinity to inhibit their function and promote debilitating paralysis at the neuromuscular junction (6, 50, 149, 264). PubMed:19126755
The first was the finding that the electric organ of a fish that produces an electric pulse to stun its prey, such as Torpedo, expresses nAChRs at densities that approach a crystalline array (245, 438). This provided an unprecedented source of starting material for receptor purification since nAChRs comprise 40% of the protein from this organ. PubMed:19126755
In fact, 80% of the synthesized subunits appear to improperly assemble or never leave the endoplasmic reticulum where they are then degraded (485). The process of retaining subunits and possibly fully assembled receptors and then degrading them may be an important component of regulating receptor number. PubMed:19126755
In fact, 80% of the synthesized subunits appear to improperly assemble or never leave the endoplasmic reticulum where they are then degraded (485). The process of retaining subunits and possibly fully assembled receptors and then degrading them may be an important component of regulating receptor number. PubMed:19126755
Neuronal nAChRs are not expressed exclusively in neurons. Instead, they are expressed by multiple cell types of diverse origins and functions including glia (165, 167, 425), keratinocytes (44, 86, 95, 426), endothelial cells (290, 495), and multiple cell types of the digestive system, lungs, and immune system (e.g., Refs. 95, 309, 492, 495). PubMed:19126755
For instance, substantial strain-specific variability in nAChR expression has been observed in the striatum (34), retina (227), cerebellum (471), and dorsal hippocampus (164, 165, 167, 169) of mice. PubMed:19126755
These results suggest that mouse strains of different genetic backgrounds undergo dissimilar age-related changes in the expression of nAChR subunits. PubMed:19126755
Not unlike snake toxins, conotoxins can disrupt multiple components of neurotransmission including voltage-gated Na+ and K+ channels in addition to nAChRs (132, 351). PubMed:19126755
Neuronal nAChRs are not expressed exclusively in neurons. Instead, they are expressed by multiple cell types of diverse origins and functions including glia (165, 167, 425), keratinocytes (44, 86, 95, 426), endothelial cells (290, 495), and multiple cell types of the digestive system, lungs, and immune system (e.g., Refs. 95, 309, 492, 495). PubMed:19126755
Neuronal nAChRs are not expressed exclusively in neurons. Instead, they are expressed by multiple cell types of diverse origins and functions including glia (165, 167, 425), keratinocytes (44, 86, 95, 426), endothelial cells (290, 495), and multiple cell types of the digestive system, lungs, and immune system (e.g., Refs. 95, 309, 492, 495). PubMed:19126755
In addition to nicotine, an nAChR agonist of considerable commercial importance is anatoxin-a (Fig. 3). This toxin is a product of the blue-green algae, Anabaena, and can reach high concentrations during algal blooms common to ponds that serve as the summer water source of livestock. While this toxin exerts much of its effect through targeting muscle nAChRs, it was recognized over two decades ago to also interact with nAChRs expressed by ganglionic receptors (38). Its ability to activate in central nervous system (CNS) neurons nicotinic currents sensitive to alpha-BGT was among the first indicators that functional alpha7 nAChRs could be distinguished from other nAChRs in neurons of the mammalian brain (38). PubMed:19126755
More recently, epibatidine, an alkaloid from the skin of the Ecuadorain tree frog Epipedobates tricolor, revealed another example of how a nicotinic agonist can produce toxic effects (111, 130). In addition to being a potent analgesic, when injected into mice at a relatively low dose (0.4 microg/mouse), this compound produced straub tail reaction. The major target of epibatidine is the alpha4beta2 high-affinity nAChR, although other nAChRs are targeted with various affinities (e.g., Ref. 507). PubMed:19126755
Additional examples of snake toxins include alpha-cobratoxin (Fig. 3), which binds to the agonist binding site of the receptor and blocks receptor activation. PubMed:19126755
Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432). PubMed:19126755
However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374). PubMed:19126755
It is noteworthy that nAChR expression by astrocytes in brains afflicted with AD is increased (463, 518), and astrocytes in general have been reported to be more plentiful in the hippocampus of some rat strains with age (35, 284). PubMed:19126755
However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374). PubMed:19126755
First, age-related nAChR subunit expression decline was observed in both strains, and this was dominated by diminished alpha4 nAChR expression. Second, long-term (12 mo) oral nicotine failed to reduce the age-related decline in the number of neurons expressing alpha4 nAChR subunits, although the neurons that remained exhibited larger processes with more varicosities than age-matched controls (165, 396). Acute nicotine treatment (alpha6 wk of oral nicotine) of aged mice had no measurable influence on nAChR expression, neuronal viability, or dendritic complexity (e.g., Ref. 396) PubMed:19126755
Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432). PubMed:19126755
Abeta1–42 activates heterologously expressed nAChRs (Dineley et al., 2002), and Abeta25–35 has been shown to activate non-alpha7 nAChRs in rat basal forebrain neurons (Fu and Jhamandas, 2003) and to evoke a alpha7- mediated calcium increases in presynaptic terminals isolated from rat hippocampus and neocortex (Dougherty et al., 2003). PubMed:19293145
There is abundant evidence that Abeta also affects cholinergic signaling in the brain. Recent studies indicate that brain nAChRs are not only affected by Abeta but can also initiate signaling pathways that protect against Abeta toxicity (Kihara et al., 1997b; Takada et al., 2003; Arias et al., 2005; Akaike, 2006; Meunier et al., 2006; Dineley, 2007; Liu et al., 2007). PubMed:19293145
Recent research interest has focused on the role of calcium dyshomeostasis in AD (Green and LaFerla, 2008); for instance, genetic links with the regulation of cytosolic calcium have been identified (Dreses- Werringloer et al., 2008). Thus nAChRs may provide a link between Abeta and disruption of calcium homeostasis. PubMed:19293145
Although there is abundant evidence that Abeta can affect nAChR function, studies disagree as to whether Abeta is an antagonist or an agonist at nAChRs (these findings are summarized in Table 1). For example, Abeta has been reported to inhibit single-channel nicotinic receptor currents in rat hippocampal interneurons (Pettit et al., 2001) as well as currents recorded from human alpha7 receptors heterologously expressed in Xenopus laevis oocytes (Tozaki et al., 2002; Grassi et al., 2003; Pym et al., 2005). Abeta, however, activates a mutant (L250T) of the alpha7 receptor—this mutant conducts current in the desensitized state, indicating that Abeta may exert its antagonistic action through receptor desensitization (Grassi et al., 2003). PubMed:19293145
Similar effects of Abeta on nAChR expression have been confirmed in studies using cultured cells; Abeta causes a reduced expression of nAChRs in PC12 cells (Guan et al., 2001), and alpha4, alpha3, and alpha7 expression are all increased in cultured rat astrocytes (Xiu et al., 2005). PubMed:19293145
Tg2576 mice expressing human Abeta show reduced [3H]cytisine binding (a label of nAChRs) in the cortex at 17 months after birth (Apelt et al., 2002). In contrast, however, levels of alpha7 or alpha4 subunits were unchanged in double-mutant Swedish APP/PS-1 mice as determined by radiolabeled cytosine (alpha4beta2) or alpha-bungarotoxin (alpha7) binding (Marutle et al., 2002). PubMed:19293145
In addition to nicotine, donepezil and rivastigmine, AChE inhibitors currently used as treatments for mild or moderate AD under the brand names of Aricept and Exelon, also protect cultured neuroblastoma cells from the toxic effects of Abeta. Although there is evidence that, in addition to inhibiting AChE, these ligands are also allosteric modulators of nAChRs (Schrattenholz et al., 1996; Coyle et al., 2007), it has not been established whether these AChE inhibitors protect neurons by their actions on alpha7 nAChRs rather than by simply inhibiting AChE, thereby elevating ACh in the medium. PubMed:19293145
In SHSY5Y cells, RNA interference (RNAi) knockdown of alpha7 enhanced Abeta toxicity (Qi et al., 2007), and alpha7 antagonists, but not alpha4beta2 antagonists, block galantamine protection of cultured rat neurons (Kihara et al., 2004). Donepezil protects cultured rat cortical neurons against Abeta toxicity through both alpha7 and non-alpha7 nAChRs (Takada et al., 2003). It is therefore likely that alpha7 nAChRs are the primary mediators of nicotine neuroprotection, but in some cells, non-alpha7 subtypes are also likely to contribute. PubMed:19293145
Nicotine stimulates the secretion of betaAPP, which is trophic and neuroprotective against Abeta, from PC12 cells through an alpha7 and calcium-dependent pathway (Kim et al., 1997) as well as increasing the secretion of soluble APP and lowering the Abeta-containing sAPP-gamma in rats (Lahiri et al., 2002), again through nAChR-dependent mechanisms. Galantamine, a nAChR potentiator and AChE inhibitor, also increases the secretion of sAPP from human SH-SY5Y neuroblastoma cells (Lenzken et al., 2007) through the activation of nAChRs. It therefore seems that activation of nAChRs shifts the balance of APP processing away from beta-amyloidogenic to soluble APP production. PubMed:19293145
The discovery that nicotine, a ligand acting at nAChRs, and its mimetics can protect neurons against Abeta toxicity (Kihara et al., 1998) is of interest, especially in view of the observation that nicotine also enhances cognition (Rusted et al., 2000). Nicotinic receptors play a particularly prominent role in nicotine protection. The protective effect is blocked by the nicotinic antagonists dihydro-beta-erythroidine and mecamylamine (Kihara et al., 2001; Takada- Takatori et al., 2006). PubMed:19293145
It is now well established that exposure to nicotine results in increased expression of nAChRs in brain and in cultured cells (for review, see Gentry and Lukas, 2002). Exposure of human neuroblastoma SH-SY5Y cells (which express ganglionic alpha7 and alpha3* nAChRs), human TE671/RD cells, or mouse BC3H-1 cells (which express muscle-type nAChRs) to nicotine for up to 120 h induces a dose- and time-dependent increase in surface ACh and alpha-bungarotoxin (alpha-BTX) binding not attributable to changes in mRNA levels (Ke et al., 1998). PubMed:19293145
In addition to nicotine, donepezil and rivastigmine, AChE inhibitors currently used as treatments for mild or moderate AD under the brand names of Aricept and Exelon, also protect cultured neuroblastoma cells from the toxic effects of Abeta. Although there is evidence that, in addition to inhibiting AChE, these ligands are also allosteric modulators of nAChRs (Schrattenholz et al., 1996; Coyle et al., 2007), it has not been established whether these AChE inhibitors protect neurons by their actions on alpha7 nAChRs rather than by simply inhibiting AChE, thereby elevating ACh in the medium. PubMed:19293145
Thus, it seems that nAChRs may play a role in mediating Abeta toxicity through synergistic mechanisms; in addition to possible direct interactions (binding), nAChRs may also result in accelerated cell death through enhancing intracellular Abeta accumulation. PubMed:19293145
Recent research interest has focused on the role of calcium dyshomeostasis in AD (Green and LaFerla, 2008); for instance, genetic links with the regulation of cytosolic calcium have been identified (Dreses- Werringloer et al., 2008). Thus nAChRs may provide a link between Abeta and disruption of calcium homeostasis. PubMed:19293145
There is evidence that ApoE directly interacts with nAChRs. An APOE-derived peptide blocks nAChRs on rat hippocampal slices with a submicromolar affinity, and this action is dependent on an arginine-rich segment of the APOE peptide (Klein and Yakel, 2004). Block of heterologously expressed alpha7 nAChRs is greater than that for alpha4beta2 or alpha2beta2 nAChRs (Gay et al., 2006). This block of alpha7 receptors is abolished when alpha7 Trp55 is mutated to alanine, providing strong evidence that it results from a direct interaction between the peptide and the receptors (Gay et al., 2007), and the effects of other substitutions of Trp55 suggests that this interaction is hydrophobic PubMed:19293145
JAK-2, another early target in the nicotine neuroprotection pathway that may mediate signaling between the nAChR and the PI3K pathway (Shaw et al., 2002), may link nAChR activation with the JAK/signal transducer and activator of transcription 3 (STAT-3) protective pathway. JAK-2 is also activated by nicotine in non-neuronal cells such as nAChR-bearing keratinocytes (Arredondo et al., 2006). In a microarray study, expression of 8 of 33 JAK/STAT pathway genes was altered when human bronchial epithelial cells were exposed to 5 microM nicotine for 4 to 10 h (Tsai et al., 2006). Thus, the JAK-2/STAT-3 pathway is activated by exposure to nicotine. PubMed:19293145
The APOE-epsilon4 gene-dose effect was also found to correlate with the loss of nAChR binding sites in patients with AD, as well as a reduced respon- siveness to the therapeutic AChE inhibitor tacrine (Poirier et al., 1995). Within an AD cohort, APOE-epsilon4 dose dependently correlates with higher losses of ChAT but not with losses in alpha4beta2 nAChRs (Lai et al., 2006). PubMed:19293145
Abeta1–42 activates heterologously expressed nAChRs (Dineley et al., 2002), and Abeta25–35 has been shown to activate non-alpha7 nAChRs in rat basal forebrain neurons (Fu and Jhamandas, 2003) and to evoke a alpha7- mediated calcium increases in presynaptic terminals isolated from rat hippocampus and neocortex (Dougherty et al., 2003). PubMed:19293145
Thus, it seems that nAChRs may play a role in mediating Abeta toxicity through synergistic mechanisms; in addition to possible direct interactions (binding), nAChRs may also result in accelerated cell death through enhancing intracellular Abeta accumulation. PubMed:19293145
AD also involves loss of neurons, beginning in the entorhinal cortex and later spreading to the neocortex (Braak et al., 2006); early in the disease, nicotinic acetylcholine receptors (nAChRs) are lost (Kadir et al., 2006). PubMed:19293145
Several lines of evidence point to a link between brain nAChRs and the development of AD. Biochemical analysis of brains of patients with AD reveals deficits in nAChRs, an increase in butyrylcholinesterase, reduction in ACh, and attenuated activity of cholinergic synthetic [choline acetyltransferase (ChAT)] and inactivating (AChE) enzymes (Bartus et al., 1982; Francis et al., 1999).Butyrylcholinesterase and AChE help terminate ACh signaling by hydrolyzing the transmitter, thereby inactivating it. PubMed:19293145
Thus, although other mechanisms are also involved in the development of AD, there is abundant evidence that defects in cholinergic synaptic transmission and, in particular, nAChR-mediated signaling plays a major role in the disease and are hence the subject of attempts to generate new routes to therapy. PubMed:19293145
It is clear that AD involves loss of cholinergic neurons in the brain as well as an overall reduction in nAChRs, and it seems that different subunits are differentially up- or down-regulated in AD in different brain regions and different cell types. PubMed:19293145
Thus, predominantly alpha4 and alpha7 subunits, and to a lesser extent alpha3 subunits, are lost in AD, although there are tissue-specific differences to this pattern, such as the upregulation of nAChRs on astrocytes. PubMed:19293145
The third important hallmark of AD is cholinergic hypofunction. The neurotransmitter acetylcholine (ACh) exerts its physiological functions by activating either ionotropic nicotinic ACh receptors (nAChRs) or metabotropic muscarinic ACh receptors (mAChRs). It has been reported that in AD brains there are (1) reduced choline acetyltransferase levels accompanied by decreased ACh synthesis; (2) significant loss of cholinergic neurons; (3) reduction in the numbers of postsynaptic neurons accessible to ACh; (4) cholinergic neuronal and axonal abnormalities; and (5) reduction in nAChR levels PubMed:24590577
The third important hallmark of AD is cholinergic hypofunction. The neurotransmitter acetylcholine (ACh) exerts its physiological functions by activating either ionotropic nicotinic ACh receptors (nAChRs) or metabotropic muscarinic ACh receptors (mAChRs). It has been reported that in AD brains there are (1) reduced choline acetyltransferase levels accompanied by decreased ACh synthesis; (2) significant loss of cholinergic neurons; (3) reduction in the numbers of postsynaptic neurons accessible to ACh; (4) cholinergic neuronal and axonal abnormalities; and (5) reduction in nAChR levels PubMed:24590577
Cholesterol is known to be crucial to nAChR function, and it interacts within the transmembrane domain between TM1, TM3 and TM4 (ReF. 57). PubMed:19721446
Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake. PubMed:19721446
Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake. PubMed:19721446
Chronic exposure to nicotine causes a striking increase, typically by twofold, in the total number of high-affinity receptors — a process termed upregulation8. PubMed:19721446
Regardless of the exact effect of Abeta1–42 on receptor activity, it does seem to block the activation by nicotine and, consistent with the cytoprotective nature of this interaction, amyloid deposition limits neuroprotection151. This phenomenon may explain at least part of the neurotoxicity that is associated with Abeta1–42 (ReF. 156). PubMed:19721446
Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake. PubMed:19721446
Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake. PubMed:19721446
Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake. PubMed:19721446
Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake. PubMed:19721446
Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake. PubMed:19721446
The nAChRs are ligand-gated ion channels that are present in both the PNS (at the skeletal neuromuscular junction and in the autonomic nervous system) and the CNS. PubMed:19721446
The nAChRs are ligand-gated ion channels that are present in both the PNS (at the skeletal neuromuscular junction and in the autonomic nervous system) and the CNS. PubMed:19721446
General anaesthetics are small hydrophobic compounds that typically allosterically inhibit nAChRs by binding to specific residues within small cavities of the TMD61,62. PubMed:19721446
Alzheimer’s disease is characterized by progressive cognitive decline, accompanied by a loss of neurons and synapses — especially cholinergic synapses — in the basal forebrain, cerebral cortex and hippocampus126 and by a substantial reduction in both muscarinic and nicotinic AChR expression127. PubMed:19721446
The first was the finding that the electric organ of a fish that produces an electric pulse to stun its prey, such as Torpedo, expresses nAChRs at densities that approach a crystalline array (245, 438). This provided an unprecedented source of starting material for receptor purification since nAChRs comprise 40% of the protein from this organ. PubMed:19126755
One insect has escaped the ill effects of nicotine, Manduca sextans or the tobacco horn worm. While nicotine binds the nAChR to activate and subsequently desensitize it, this insect eats the tobacco plant without ill effects. Manduca exhibits two adaptations to tolerate the effects of nicotine. The first is altered nAChR amino acid sequences that limit the affinity of nicotine for the nAChR (136). The second is the development of the functional equivalent to a blood-brain barrier. PubMed:19126755
Third, nAChR-mediated GABA release can cause neuronal hyperpolarization, which in turn affects neuronal function via several mechanisms, including removal of inactivation of inward currents (89). PubMed:19126755
In the basal ganglia, for instance, dopaminergic transmission is ultimately regulated by the activity of specific nAChR subtypes in different neurons and neuronal compartments (Fig. 5). Thus evidence exists that in the VTA,alpha6- andalpha4-containing nAChRs are mainly located on dopaminergic nerve terminals, whereas alpha7 nAChRs are primarily expressed on the soma of dopaminergic neurons (Fig. 5). PubMed:19126755
Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432). PubMed:19126755
However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374). PubMed:19126755
It is noteworthy that nAChR expression by astrocytes in brains afflicted with AD is increased (463, 518), and astrocytes in general have been reported to be more plentiful in the hippocampus of some rat strains with age (35, 284). PubMed:19126755
Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432). PubMed:19126755
Of note is that in both of these catastrophic disorders, reduced nAChR activity/expression is accompanied by increased levels of kynurenic acid (KYNA), a tryptophan metabolite that in the brain is primarily produced and released by astrocytes (244, 419). PubMed:19126755
Other endogenous ligands that impact on the activity of nAChRs noncompetitively and voltage independently include the amyloid beta peptide 1-42 (Abeta1-42; Refs. 123, 376) and the canabinoid anandamide (356, 442). PubMed:19126755
Other endogenous ligands that impact on the activity of nAChRs noncompetitively and voltage independently include the amyloid beta peptide 1-42 (Abeta1-42; Refs. 123, 376) and the canabinoid anandamide (356, 442). PubMed:19126755
Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443). PubMed:19126755
It has long been recognized that nAChR activation in mammalian sympathetic neurons induces the opening of a nonselective cation channel that leads to Na+ influx, membrane depolarization, and consequently activation of voltage-gated Ca2+ channels (92, 119). PubMed:19126755
It has long been recognized that nAChR activation in mammalian sympathetic neurons induces the opening of a nonselective cation channel that leads to Na+ influx, membrane depolarization, and consequently activation of voltage-gated Ca2+ channels (92, 119). PubMed:19126755
It has long been recognized that nAChR activation in mammalian sympathetic neurons induces the opening of a nonselective cation channel that leads to Na+ influx, membrane depolarization, and consequently activation of voltage-gated Ca2+ channels (92, 119). PubMed:19126755
It has long been recognized that nAChR activation in mammalian sympathetic neurons induces the opening of a nonselective cation channel that leads to Na+ influx, membrane depolarization, and consequently activation of voltage-gated Ca2+ channels (92, 119). PubMed:19126755
Long before the identification of the high Ca2+ permeability of alpha7 nAChR channels, different studies reported significant Ca2+ influx through nAChRs in muscle, parasympathetic neurons, pheochromocytoma cells, and human neuroblastoma cells (115, 321, 347, 407, 411, 459, 468). PubMed:19126755
There is current evidence that nAChRs present in skin cells modulate the responses triggered by inflammatory stimuli applied to the skin (354). Smoking is a welldefined risk factor in delayed wound healing and possibly the development of premature facial wrinkling (226). PubMed:19126755
Mechanistically, nicotine, acting through nAChRs, decreases keratinocyte migration (188, 189) and modifies the activity of PI3K/Akt, ERK, MEK, and JAK signaling pathways. PubMed:19126755
Mechanistically, nicotine, acting through nAChRs, decreases keratinocyte migration (188, 189) and modifies the activity of PI3K/Akt, ERK, MEK, and JAK signaling pathways. PubMed:19126755
Mechanistically, nicotine, acting through nAChRs, decreases keratinocyte migration (188, 189) and modifies the activity of PI3K/Akt, ERK, MEK, and JAK signaling pathways. PubMed:19126755
Mechanistically, nicotine, acting through nAChRs, decreases keratinocyte migration (188, 189) and modifies the activity of PI3K/Akt, ERK, MEK, and JAK signaling pathways. PubMed:19126755
For instance, substantial strain-specific variability in nAChR expression has been observed in the striatum (34), retina (227), cerebellum (471), and dorsal hippocampus (164, 165, 167, 169) of mice. PubMed:19126755
These results suggest that mouse strains of different genetic backgrounds undergo dissimilar age-related changes in the expression of nAChR subunits. PubMed:19126755
Strain-dependent variations in nAChR density in regions of the rat brain have also been reported. PubMed:19126755
However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374). PubMed:19126755
There is abundant evidence that Abeta also affects cholinergic signaling in the brain. Recent studies indicate that brain nAChRs are not only affected by Abeta but can also initiate signaling pathways that protect against Abeta toxicity (Kihara et al., 1997b; Takada et al., 2003; Arias et al., 2005; Akaike, 2006; Meunier et al., 2006; Dineley, 2007; Liu et al., 2007). PubMed:19293145
Recent research interest has focused on the role of calcium dyshomeostasis in AD (Green and LaFerla, 2008); for instance, genetic links with the regulation of cytosolic calcium have been identified (Dreses- Werringloer et al., 2008). Thus nAChRs may provide a link between Abeta and disruption of calcium homeostasis. PubMed:19293145
In addition to Abeta acting upon nAChRs, nAChRs in turn regulate Abeta secretion. Nicotine or epibatidine applied to the human SHEP1 cell line stably transfected with human alpha4beta2 nAChRs and human APP decreases the secretion and intracellular accumulation of Abeta without significantly affecting the APP mRNA, suggesting that these effects are post-translational (Nie et al., 2007). PubMed:19293145
Thus, it seems that nAChRs may play a role in mediating Abeta toxicity through synergistic mechanisms; in addition to possible direct interactions (binding), nAChRs may also result in accelerated cell death through enhancing intracellular Abeta accumulation. PubMed:19293145
Although there is abundant evidence that Abeta can affect nAChR function, studies disagree as to whether Abeta is an antagonist or an agonist at nAChRs (these findings are summarized in Table 1). For example, Abeta has been reported to inhibit single-channel nicotinic receptor currents in rat hippocampal interneurons (Pettit et al., 2001) as well as currents recorded from human alpha7 receptors heterologously expressed in Xenopus laevis oocytes (Tozaki et al., 2002; Grassi et al., 2003; Pym et al., 2005). Abeta, however, activates a mutant (L250T) of the alpha7 receptor—this mutant conducts current in the desensitized state, indicating that Abeta may exert its antagonistic action through receptor desensitization (Grassi et al., 2003). PubMed:19293145
There is abundant evidence that Abeta also affects cholinergic signaling in the brain. Recent studies indicate that brain nAChRs are not only affected by Abeta but can also initiate signaling pathways that protect against Abeta toxicity (Kihara et al., 1997b; Takada et al., 2003; Arias et al., 2005; Akaike, 2006; Meunier et al., 2006; Dineley, 2007; Liu et al., 2007). PubMed:19293145
Thus, it seems that nAChRs may play a role in mediating Abeta toxicity through synergistic mechanisms; in addition to possible direct interactions (binding), nAChRs may also result in accelerated cell death through enhancing intracellular Abeta accumulation. PubMed:19293145
Thus, although other mechanisms are also involved in the development of AD, there is abundant evidence that defects in cholinergic synaptic transmission and, in particular, nAChR-mediated signaling plays a major role in the disease and are hence the subject of attempts to generate new routes to therapy. PubMed:19293145
The discovery that nicotine, a ligand acting at nAChRs, and its mimetics can protect neurons against Abeta toxicity (Kihara et al., 1998) is of interest, especially in view of the observation that nicotine also enhances cognition (Rusted et al., 2000). Nicotinic receptors play a particularly prominent role in nicotine protection. The protective effect is blocked by the nicotinic antagonists dihydro-beta-erythroidine and mecamylamine (Kihara et al., 2001; Takada- Takatori et al., 2006). PubMed:19293145
For example, non-alpha7 nAChRs protect cultured nigral dopaminergic neurons from toxicity induced by 1-methyl-4-phenylpyridinium, a neurotoxin that selectively damages nigrostriatal dopaminergic neurons (Jeyarasasingam et al., 2002), and this effect is not mediated by alpha7 receptors. PubMed:19293145
Likewise, blocking the PI3K-AKT pathway inhibits the protective effects of AChE inhibitors on neuroblastoma cells or neuronal cells against Abeta (Arias et al., 2005) or L-glutamate neurotoxicity (Takada-Takatori et al., 2006). In all these studies, protection was also inhibited by nAChR blockers, suggesting that these effects are mediated by nAChRs. PubMed:19293145
For instance, over-expressing PI3K in Drosophila melanogaster neurons in situ results in an increase in functional synapses as well as synaptic sprouting (Martín-Pen˜ a et al., 2006). Thus it is possible that nicotine’s activation of the PI3K pathway results in increased synaptic stability, and it would be of interest to explore this further in vertebrates. Thus, the evidence suggests that activation of nAChRs activates the PI3K/AKT pathway to favor antiapoptotic pathways and possibly induce synaptogenesis. PubMed:19293145
JAK-2, another early target in the nicotine neuroprotection pathway that may mediate signaling between the nAChR and the PI3K pathway (Shaw et al., 2002), may link nAChR activation with the JAK/signal transducer and activator of transcription 3 (STAT-3) protective pathway. JAK-2 is also activated by nicotine in non-neuronal cells such as nAChR-bearing keratinocytes (Arredondo et al., 2006). In a microarray study, expression of 8 of 33 JAK/STAT pathway genes was altered when human bronchial epithelial cells were exposed to 5 microM nicotine for 4 to 10 h (Tsai et al., 2006). Thus, the JAK-2/STAT-3 pathway is activated by exposure to nicotine. PubMed:19293145
Recent research interest has focused on the role of calcium dyshomeostasis in AD (Green and LaFerla, 2008); for instance, genetic links with the regulation of cytosolic calcium have been identified (Dreses- Werringloer et al., 2008). Thus nAChRs may provide a link between Abeta and disruption of calcium homeostasis. PubMed:19293145
The APOE-epsilon4 gene-dose effect was also found to correlate with the loss of nAChR binding sites in patients with AD, as well as a reduced respon- siveness to the therapeutic AChE inhibitor tacrine (Poirier et al., 1995). Within an AD cohort, APOE-epsilon4 dose dependently correlates with higher losses of ChAT but not with losses in alpha4beta2 nAChRs (Lai et al., 2006). PubMed:19293145
There is evidence that ApoE directly interacts with nAChRs. An APOE-derived peptide blocks nAChRs on rat hippocampal slices with a submicromolar affinity, and this action is dependent on an arginine-rich segment of the APOE peptide (Klein and Yakel, 2004). Block of heterologously expressed alpha7 nAChRs is greater than that for alpha4beta2 or alpha2beta2 nAChRs (Gay et al., 2006). This block of alpha7 receptors is abolished when alpha7 Trp55 is mutated to alanine, providing strong evidence that it results from a direct interaction between the peptide and the receptors (Gay et al., 2007), and the effects of other substitutions of Trp55 suggests that this interaction is hydrophobic PubMed:19293145
Nicotine stimulates the secretion of betaAPP, which is trophic and neuroprotective against Abeta, from PC12 cells through an alpha7 and calcium-dependent pathway (Kim et al., 1997) as well as increasing the secretion of soluble APP and lowering the Abeta-containing sAPP-gamma in rats (Lahiri et al., 2002), again through nAChR-dependent mechanisms. Galantamine, a nAChR potentiator and AChE inhibitor, also increases the secretion of sAPP from human SH-SY5Y neuroblastoma cells (Lenzken et al., 2007) through the activation of nAChRs. It therefore seems that activation of nAChRs shifts the balance of APP processing away from beta-amyloidogenic to soluble APP production. PubMed:19293145
Thus, it seems that nAChRs may play a role in mediating Abeta toxicity through synergistic mechanisms; in addition to possible direct interactions (binding), nAChRs may also result in accelerated cell death through enhancing intracellular Abeta accumulation. PubMed:19293145
It is also noteworthy that Abeta-induced tau protein phosphorylation in PC12 cells is inhibited not only by alpha7 agonists, as would be predicted from the role of alpha7 nAChRs in neuroprotection, but also by alpha-bungarotoxin (Hu et al., 2008), as might be predicted if the competition by alpha-bungarotoxin for the Abeta site blocked a direct action of Abeta on nAChRs. It is therefore possible that the toxicity of Abeta is mediated, at least in part, through a direct physical interaction between Abeta and nAChRs. PubMed:19293145
Acetylcholine (ACh) is a neurotransmitter that modulates neuronal function in several areas of the CNS associated with AD and/or SZ pathology, including the striatum, cortex, hippocampus, and prefrontal cortex.5 ACh mediates its actions via two families of receptors, termed the muscarinic ACh receptors (mAChRs) and the nicotinic ACh receptors (nAChRs). PubMed:24511233
ACh is produced by the enzyme choline acetyltransferase and its actions are mediated through two types of acetylcholine receptors (AChRs) — the G protein-coupled muscarinic AChRs and the nicotinic AChRs (nAChRs). PubMed:19721446
The nAChRs are ligand-gated ion channels that are present in both the PNS (at the skeletal neuromuscular junction and in the autonomic nervous system) and the CNS. PubMed:19721446
The nAChRs are ligand-gated ion channels that are present in both the PNS (at the skeletal neuromuscular junction and in the autonomic nervous system) and the CNS. PubMed:19721446
Typically, activation of brain nAChRs results in enhanced release of various key neurotransmitters, including dopamine, serotonin, glutamate and GABA (gamma-aminobutyric acid). PubMed:19721446
Typically, activation of brain nAChRs results in enhanced release of various key neurotransmitters, including dopamine, serotonin, glutamate and GABA (gamma-aminobutyric acid). PubMed:19721446
Typically, activation of brain nAChRs results in enhanced release of various key neurotransmitters, including dopamine, serotonin, glutamate and GABA (gamma-aminobutyric acid). PubMed:19721446
Typically, activation of brain nAChRs results in enhanced release of various key neurotransmitters, including dopamine, serotonin, glutamate and GABA (gamma-aminobutyric acid). PubMed:19721446
Cholesterol is known to be crucial to nAChR function, and it interacts within the transmembrane domain between TM1, TM3 and TM4 (ReF. 57). PubMed:19721446
nAChRs are known to control sensory gating, and studies investigating the role of nAChRs in schizophrenia have focused primarily on alpha7 nAChRs. Sensory-gating deficits in patients with schizophrenia174 have been linked to chromosome 15q14, proximal to the alpha7 locus175,176. PubMed:19721446
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