Certain neurotoxins work by inhibiting acetylcholinesterase, leading to excess acetylcholine at the neuromuscular junction. This results in paralysis of the muscles needed for breathing and stops the beating of the heart. Adrenergic receptors are molecules that bind catecholamines. Their activation leads to overall stimulatory and sympathomimetic responses. The adrenergic receptors or adrenoceptors are a class of metabotropic G protein -coupled receptors that are targets of the catecholamines, especially norepinephrine or noradrenaline, and epinephrine adrenaline.
Although dopamine is a catecholamine, its receptors are in a different category. Many cells possess these receptors, and the binding of an agonist will generally cause a sympathetic or sympathomimetic response e. For instance, the heart rate will increase, pupils will dilate, energy will be mobilized, and blood flow will be diverted from non-essential organs to skeletal muscle.
Adrenaline epinephrine : The 2D structure of adrenaline epinephrine is illustrated. Noradrenaline norepinephrine : The 2D structure of noradrenaline norepinephrine is illustrated here. Agonist binding thus causes a rise in the intracellular concentration of the second messenger cAMP. Isoprenaline is a nonselective agonist. Adrenergic signal transduction : This schematic shows the mechanism of adrenergic receptors. The result is that high levels of circulating epinephrine cause vasoconstriction.
Smooth muscle behavior is variable depending on anatomical location. One important note is the differential effects of increased cAMP in smooth muscle compared to cardiac muscle. Increased cAMP will promote relaxation in smooth muscle, while promoting increased contractility and pulse rate in cardiac muscle. Common or still unspecified effects include: vasoconstriction of cardiac arteries coronary artery , vasoconstriction of veins, and decreased motility of smooth muscle in the gastrointestinal tract.
The former interacts with calcium channels of the endoplasmic and sarcoplasmic reticulum, thus changing the calcium content in a cell. This triggers all other effects. It causes vasoconstriction in many blood vessels, including those of the skin, gastrointestinal system, kidney renal artery , and brain. Other areas of smooth muscle contraction are:.
Antagonists may be used in hypertension. Drugs effecting cholinergic neurotransmission may block, hinder, or mimic the action of acetylcholine and alter post-synaptic transmission. Distinguish between the effects of an agonist versus an antagonist in the autonomic nervous system. Blocking, hindering, or mimicking the action of acetylcholine has many uses in medicine. Drugs that act on the acetylcholine system are either agonists to the receptors that stimulate the system, or antagonists that inhibit it.
Acetylcholine receptor agonists and antagonists can have a direct effect on the receptors or exert their effects indirectly. For example, by affecting the enzyme acetylcholinesterase the receptor ligand is degraded. Agonists increase the level of receptor activation, antagonists reduce it. The vagus parasympathetic nerves that innervate the heart release acetylcholine ACh as their primary neurotransmitter.
ACh binds to muscarinic receptors M2 that are found principally on cells comprising the sinoatrial SA and atrioventricular AV nodes. Muscarinic receptors are coupled to the G i -protein; therefore, vagal activation decreases cAMP. G i -protein activation also leads to the activation of KACh channels that increase potassium efflux and hyperpolarizes the cells. Increases in vagal activity to the SA node decreases the firing rate of the pacemaker cells by decreasing the slope of the pacemaker potential and decreasing heart rate.
Similar electrophysiological effects also occur at the atrioventricular AV node. However, in this tissue, these changes are manifested as a reduction in impulse conduction velocity through the AV node. In the resting state, there is a large degree of vagal tone on the heart, which is responsible for low, resting heart rates. There is also some vagal innervation of the atrial muscle, and to a much lesser extent, the ventricular muscle.
Vagus activation, therefore, results in modest reductions in atrial contractility inotropy and even smaller decreases in ventricular contractility. Atropine : The 2D chemical structure of atropine is illustrated here. Muscarinic receptor antagonists bind to muscarinic receptors, thereby preventing ACh from binding to and activating the receptor. By blocking the actions of ACh, muscarinic receptor antagonists very effectively block the effects of vagal nerve activity on the heart.
By doing so, they increase heart rate and conduction velocity. Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade Atropa belladonna , Jimson weed Datura stramonium , mandrake Mandragora officinarum , and other plants of the family Solanaceae. It is an anti-muscarinic agent. Working as a nonselective muscarinic acetylcholinergic antagonist, atropine increases firing of the sinoatrial node SA and conduction through the atrioventricular node AV of the heart, opposes the actions of the vagus nerve, blocks acetylcholine receptor sites, and decreases bronchial secretions.
In overdoses, atropine is poisonous. A nicotinic agonist is a drug that mimics, in one way or another, the action of acetylcholine ACh at nicotinic acetylcholine receptors nAChRs. Nicotinic acetylcholine receptors are receptors found in the central nervous system, the peripheral nervous systems, and skeletal muscles.
They are ligand-gated ion channels with binding sites for acetylcholine as well as other agonists. When agonists bind to a receptor it stabilizes the open state of the ion channel allowing an influx of cations. Nicotinic acetylcholine receptors: NAchR are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction. Nicotinic antagonists are mainly used for peripheral muscle paralysis in surgery, the classical agent of this type being tubocurarine, but some centrally acting compounds such as bupropion, mecamylamine, and methoxycoronaridine block nicotinic acetylcholine receptors in the brain and have been proposed for treating drug addiction.
In there were at least five drugs on the market that affect the nicotinic acetylcholine receptors. Most indirect-acting ACh receptor agonists work by inhibiting the enzyme acetylcholinesterase. The resulting accumulation of acetylcholine causes a continuous stimulation of the muscles, glands, and central nervous system. They are examples of enzyme inhibitors, and increase the action of acetylcholine by delaying degradation; some have been used as nerve agents sarin and VX nerve gas or pesticides organophosphates and the carbamates.
They are particularly used for the management of cardiac arrhythmias, cardiac protection after myocardial infarction heart attack , and hypertension. As beta-adrenergic receptor antagonists, they diminish the effects of epinephrine adrenaline and other stress hormones. Privacy Policy. Skip to main content. Autonomic Nervous System. ACh [ 46 ] is present in the brain prior to axonogenesis and synaptogenesis, suggesting that it may mediate non-classical signaling.
Furthermore, muscarinic receptors are widely expressed in embryonic cells [ 8 , 13 , 47 — 54 ], and have been shown to regulate neuronal cell proliferation and differentiation [ 47 , 50 , 51 ]. In neuronal progenitor cells, muscarinic receptor expression also occurs prior to the onset of synaptogenesis and neurotransmission [ 9 , 55 ], indicating that ACh may act via a local autocrine loop in the embryo.
In early development, M2 receptors are expressed in the dorsal root ganglia neurons, as well as in non-neural cells such as Schwann cells, where they control sensory neuronal differentiation and axonal growth [ 56 ].
Intriguingly, muscarinic receptors are also expressed in primary and metastatic tumor cells in which ACh also acts in an autocrine fashion [ 57 ]. As discussed above, expression of muscarinic receptors is an embryonic trait.
The expression of these receptors in tumor cells [ 8 , 13 , 58 — 63 ] likely arises from reactivation of embryonic genes during malignant growth [ 52 ]. Proliferation due to mAChR activation has been reported in many tumor cells. For example, activation of muscarinic M1, M3 or M5 muscarinic receptors but not M2 or M4 receptors induces foci of transformation in 3T3 cells [ 64 , 65 ]. These effects of muscarinic receptor activation depend on the cellular phenotype [ 70 , 71 ].
Activation of M3 induces proliferation in human colon cancer cell lines and prostate carcinoma cells [ 72 ]. In contrast, activation of endogenous M3 inhibits DNA synthesis in several small cell lung carcinoma cell lines [ 72 ].
These contradictory responses also occur in cells transfected with mAChRs, as transfected M3 mAChRs has been reported to both inhibit and stimulate proliferation [ 73 — 75 ]. In cells deprived of trophic factors, muscarinic M3 receptor activation elicits anti-proliferative signals via activation of the small GTP-binding protein, Rac1 [ 72 , 76 , 77 ].
However, muscarinic agonists can also inhibit apoptosis. Pretreatment of tumor cell lines with muscarinic agonists inhibits apoptosis induced by DNA damage [ 78 — 81 ]. Moreover, agonists for M1, M3 and M5 subtypes showed a protective response against apoptosis in Chinese hamster ovary cells transfected with these muscarinic receptors [ 82 ].
It is unclear whether muscarinic receptor activation is related to tumor growth and stem cell proliferation [ 8 , 84 — 87 ]. In addition to morphogenesis, non-neuronal muscarinic receptors also control cell migration, as M3, M4 and M5 subtypes were shown to control cell migration by facilitating fibronectin-induced movement [ 58 , 88 — 90 ].
Contraction and aggregation of cells in embryonic tissue is also induced by muscarinic receptor activation [ 91 ]. In this way, mAChRs could modulate cellular movement during morphogenesis [ 92 , 93 ]. Many G-protein-coupled receptors protect cells from apoptosis induced by growth factors, DNA damage or cellular stress.
Among those receptors, mAChRs have been shown to be protective in many cell lines and primary cell cultures [ 8 , 78 — 80 , 94 , 95 ]. These reports raise the possibility that damage to cholinergic pathways might contribute to the development of neurodegenerative disorders, such as Alzheimer and Huntington. In some neurodegenerative disorders losses of neuronal survival stimuli occur, leading to cell death.
These kinases activate pro-survival pathways in diverse cell types [ 96 ], including neurons [ 97 , 98 ]. Previous work [ 77 , 80 , 99 — ] has demonstrated that Akt can be activated effectively through G q coupled to M1 and M3, and G i coupled to M2.
Interestingly, Lindenboim et al. Previous reports have described cholinergic signaling in progenitor and tumoral cells. Similar results were also obtained in non-neuronal cell types [ — ]. Although it is unclear if mAChR activation is related to oncogenic progression, there are reports suggesting that inhibition of mAChRs decrease cell proliferation [ 8 , ].
In line with these results, previous work showed that apoptosis can be induced in Chinese hamster ovary cells transfected with the M3 receptor and exposed to toxic substances [ 83 ]. This effect might be related to caspase action, considering that M3 receptor activation did not prevent cell death. However, the use of a version of M3 truncated at its carboxyl end revealed that this protection is not mediated by PLC or by phosphorylation of its receptor.
Moreover, these pathways are not involved in activation of ERK and JNK, so presumably, the anti-apoptotic actions of mAChRs are not mediated by these proteins, but through its own C terminal domain, which is rich in basic residues [ 83 ]. The mechanism through which mAChRs mediate cell survival is dependent on transcription of the anti-apoptotic protein Bcl-2, which can be induced by mAChRs [ 83 ]. This protective feature of mAChRs may be a conserved among other G-protein coupled receptors.
See text for a better description. It has been suggested that these pathways inhibit caspases [ 77 , 79 , ]. Furthermore, previous studies in PC12 cells have shown that these inhibitors block survival effects and ERK and PI3-kinase signaling [ , ]. However, it was shown that pertussis toxin did not inhibit Akt phosphorylation. Upon activation, the TrkA receptor activates the PI3-K pathway, leading to activation of Akt in sympathetic neurons [ ].
Furthermore, there is prior evidence pointing to a functional association between pertussis toxin-sensitive G proteins and growth factor receptors such as the insulin receptor tyrosine kinase [ ]. In addition, some pertussis toxin-sensitive growth factor-induced responses have been reported. Increasing evidence shows that GPCRs often cooperate with RTKs receptor tyrosine kinases in the regulation of numerous signal transduction pathways [ — ].
More recently, a report has demonstrated that NGF and lysophosphatidate receptor signaling systems can interact to promote G protein-mediated activation of the Erk pathway [ ].
One candidate for mediating the muscarinic effect on caspases is sphingosinephosphate, which was shown to play an important role in the survival effect of NGF on PC12 cells [ ]. Interestingly, sphingosinephosphate can be induced by the M2 muscarinic receptor [ ]. Intriguingly, inhibition of the PI3-kinase pathway partially attenuates the muscarinic survival effect on the viability of the cells but not on caspase inhibition.
One possible explanation is that serum-deprived cells can die via both caspase-dependent and -independent pathways, as shown in some apoptotic paradigms such as Bax-induced cell death in the presence of caspase inhibitors [ — ].
Despite the fact that the caspase-dependent pathway seems to play a major role in the death of serum-deprived PC12 cells, it is possible that once this pathway is inhibited, the caspase-independent pathway has a major role.
However, one cannot exclude the possibility that there are unknown caspases which are activated and involved in apoptosis induced by trophic-factor-deprivation and that these caspases are inhibited by the muscarinic receptor in a different mechanism than that used to inhibit the DEVDase caspases and caspase It was shown that NGF withdrawal from differentiated PC12 cells induces expression of FasL, which in turn may contribute to the apoptotic process via activation of the CD95 receptor [ , ].
In this case, it is still possible that muscarinic receptors will inhibit the activation of caspase-8, the caspase which is directly activated when CD95 is activated [ 80 , , ] by a PI3-kinase-dependent mechanism as was shown for CD3 activation in Fas-treated Th2-type cells [ 80 , ].
In some systems, one signaling pathway appears to be sufficient for mediating survival induced by trophic agents such as NGF PI3-kinase and N -acetylcysteine ERK [ , ]. However, in other systems, the survival effect may require the combined action of several signaling pathways. It has been suggested that the muscarinic survival effect could be mediated by the combined effect of at least two different pathways.
The other pathway would act through G q and may involve the PI3-kinase pathway, and could promote survival by a mechanism that does not affect caspases and that could be mediated by the G q -coupled receptors.
Previous reports showed that muscarinic receptor stimulation leads to activation of the Rho family of small G-proteins [ , ]. This pathway can lead to activation of Rho kinase [ ] and is critical for the protective capacity of muscarinic receptors. However, an increase of M1-SRF signaling inhibition was observed when intracellular calcium was decreased. Nicotinic receptors are expressed in neural and non-neuronal tissues; however, in the latter their function is not clear.
Although nAChRs are primarily known for their action as ligand-gated ion channels transducing action potentials across synapses, they may have other actions as well, such as cell-to-cell communications in various non-neuronal tissues controling important cell functions such as proliferation, adhesion, migration, secretion, survival and apoptosis in an autocrinal, justacrinal and paracrinal manner [ 22 ].
Interestingly, nicotinic receptors in neurons protect against cell death in some settings [ 8 , 12 , 68 , 81 ]. One pathway involved in AKT signaling involves phosphorylation of the forkhead transcription factor FKHRL1, causing its retention in the cytoplasm associated with This in turn blocks expression of the apoptotic protein fas [ ]. If so, nicotinic agents may prove useful in the treatment of this and other neurodegenerative conditions.
It was shown that an inhibitor of Src tyrosine kinase also reduced Akt phosphorylation. Therefore, nicotinic receptor stimulation might lead to phosphorylation of Akt through Fyn [ — ]. Figures 1 and 2. Nicotine has also been shown to regulate the Bcl-2 family of proteins. For example, nicotine induces phosphorylation of Bcl-2 leading to protection of human small cell lung carcinoma cells against cisplatin-induced apoptosis [ , ]. Diagram depicting proliferative and survival signaling pathways in cells.
In vitro , the homomeric and heteromeric nAChRs jointly stimulate the indicated signaling cascades. Yellow arrows indicate proliferative pathways triggered by nAChRs. Sustained mitogenic signaling induces to S-phase entry. The protective effects of nicotine have been studied in NSCLC and PC12 cell lines, as well as in other experimental systems [ — ]. Furthermore, administration of nicotine in the CNS can stimulate release of neurotransmitters [ , ] and neurotrophic factors, such as basic fibroblast growth factor bFGF or FGF-2 and brain-derived neurotrophic factor BDNF [ ].
In addition, nicotine exposure can lead to elevated cellular cAMP levels [ ]. It was demonstrated that nicotine attenuates both arachidonic acid-induced caspase activation and apoptosis of spinal cord neurons [ ]. However, controversy exists on the specific nAChR subunit responsible for the anti-apoptotic effects of nicotine. These data demonstrate that during differentiation there are changes in nAChR activity and function. Such discrepancies can be partially explained by the pleiotropic nature of nAChR subunit inhibitors.
It is also possible that the anti-apoptotic effects of nicotine are mediated by different nAChR subunits in a tissue-specific manner. These possibilities underscore the need for further studies to identify the nAChR subunits responsible for the anti-apoptotic effects of nicotine. Previous reports showed that ERK2 can increase expression of bcl-2 and inhibit apoptosis [ ].
In addition, the neuroprotective effects of ERK1 and ERK2 may be related to activation of a variety of transcription factors, which in turn can regulate transcription of neurotrophic factors, leading to overexpression of "survival" genes and enhanced neuronal viability. In addition, recent evidence indicates that CREB has a crucial role in regulation of cell viability [ ], as it is required to induce transcription of BDNF [ ]. Elk1 functions as a nuclear transcriptional activator through the interaction with the serum response element SRE , which is present in the promoter of many immediate early genes [ ].
Among others, Elk1 is involved in regulation of expression of FGF-2 [ , ]. Previous studies have demonstrated that proliferation and differentiation of neuronal precursor cells can be modulated by mAChR signaling [ 8 , 13 , , ]. Transient calcium increases induced by ACh independently of MAPk activation has been shown to be necessary for differentiation and proliferation, as muscarinic antagonists and calcium chelating agents block these effects Figures 3 and 4 [ 8 , 13 ].
Muscarinic and nicotinic receptor-coupled signal transduction pathways mediating MAPK activity and proliferation. Calcium signaling pathways in stem cells and neural progenitor cells. Left panel represents a embryonic or adult stem cells and right panel the neuronal progenitor cells. Calcium from the ER is released by two types of channels, Inositol 1,4,5-trisphosphate IP3 channels and ryanodine channels.
The first is present in both neural progenitor and stem cells, while the latter is expressed only in nural progenitor cells. Activation of M2 and M3 receptors has been shown to increase proliferation of tumoral cells in a dose-dependent manner. Cellular proliferation induced by the M3 subtype is mediated by production of inositol triphosphate, [ 8 , 66 ] and nitric oxide [for a review see [ ]], while the effects of the M2 subtype were dependent on concomitant activation of M1, promoting the release of E2 prostaglandin and arginase catabolism.
These events are related to tumoral cell growth [ 66 ], and inhibition of caspases [ 79 , 83 ]. In murine mammary adenocarcionoma cells, the M3 subtype is the most highly expressed muscarinic receptor. Each of these molecules in turn activates different pathways. Activation of this pathway increases protein synthesis and cell proliferation through MAPK kinase, besides inducing DNA synthesis in neuronal progenitor cells during early neurogenesis [ ].
Cells in the neuroepithelial ventricular zone of the embryonic rat cortex also express the M2 receptor. The presence of M2 induces cell proliferation and accelerates neuronal differentiation. Adrenergic receptors can transform fibroblasts when actively mutated [ ]. Interestingly, transformation by mAChRs was ligand-dependent [ ]. Furthermore, some viruses encode constitutively active GPCRs linked to cell proliferation for a review see [ , ] , suggesting that signals initiated by GPCRs can be mitogenic.
MAPKs target numerous cellular proteins and transcription factors involved in cell growth and differentiation [ — ]. The vast majority of the currently described pathways leading to ERK stimulation have been considered as linear. However, Blaukat et al. Muscarinic receptors in many cells have been shown to activate ERK by carbachol, and this is not altered by treatment with pertussis toxin, indicating that Gq-, but not Gi-protein, may be involved in ERK activation [ 61 , — ].
Moreover, the Src family of protein tyrosine kinases has been implicated in mAChR-induced ERK activation in different cell lines [ — ]. Further studies are needed to determine the connection between activation of these protein tyrosine kinases and the downstream effects of mAChR after G protein activation.
It has been suggested that carbachol's effects on ERK1 and ERK2 phosphorylation were probably mediated through the activation of protein tyrosine kinases. Previous reports have shown that nAChRs are expressed in non-neuronal cells within the nervous system [ , ], embryonic stem cells [ 8 , 13 ], neural stem cells [ ], and embryonic tissues [ ]. Nicotinic receptors are also expressed on O2A oligodendrocyte precursors, but are not detectable after induction of differentiation, indicating that nAChR expression is developmentally controlled in these cells [ ].
Although the physiological functions of nAChRs in O2A oligodendrocyte precursors are not understood, data suggest that activation of nAChRs might control migration, survival and differentiation in these cells [ ]. Since nAChRs do not have intrinsic tyrosine kinase activity [ 22 ], the molecular mechanisms underlying its effects on proliferation remain unclear.
This in turn leads to binding of Raf-1 kinase to Rb, leading to cell cycle entry [ ]. Dasgupta and coworkers demonstrated that human non-small cell lung cancer NSCLC tumor tissues had high levels of Rb-Raf-1 complexes in tumors relative to adjacent normal lung tissue, suggesting that perhaps the Rb-Raf-1 pathway contributes to the genesis of these tumors. The subsequent steps resemble growth factor-induced cell proliferation, as they include activation of Src, association of Rb to Raf-1, inactivation of Rb, and enhanced recruitment of E2F1 and Raf-1 to promoters of genes that induce proliferation [ ].
These events are likely to contribute to the growth and progression of tumoral cells. As previously demonstrated [ 8 , 13 ], AChRs have different roles on proliferation in embryonic and neural stem cells. In embryonic cells, nAChRs decrease proliferation. These pharmacological agents include any substance that acts through AChR activation or through pathways activated by them.
The examples described here to modulate proliferation, differentiation, and genetic modification of neural stem cells in vitro can be adapted to in vivo techniques.
Such in vivo manipulation and modification of these cells allows cells lost due to injury or disease to be endogenously replaced. This would abolish the need for transplanting foreign cells into a patient. Additionally, cells can be modified or genetically engineered in vivo so that they express various biological agents useful in the treatment of neurological disorders.
However, fine control of muscarinic signaling requires compounds that selectively modulate specific muscarinic receptor subtypes. Unfortunately, such drugs have not been discovered yet.
M1 muscarinic agonists such as arecoline have also been found to be weak agonists of M2 and M3 subtypes, and are not very effective in treating cognitive impairment, most likely because of dose-limiting side effects [ , ]. Treatment with nicotinic receptor agonists also has therapeutic potential, similarly to muscarinic agonists. However, nAChR agonists which bind the same site as ACh are not a viable solution, for ACh not only activates, but also blocks receptor activity through desensitization [ ] and uncompetitive blockade [for review see [ ]].
Furthermore, prolonged activation appears to induce a long-lasting inactivation. Therefore, agonists of ACh may reduce or enhance receptor activation. In nAChRs, desensitization generally limits the duration of current during agonist application [ ]. However, positive allosteric modulators can enhance the efficacy of agonists at nicotinic receptors. It is believed that such compounds would be useful for treatment of conditions associated with decreased nicotinic transmission.
In a therapeutic setting, these compounds could restore normal interneuronal communication without affecting the temporal profile of activation. In addition, they would not produce long-term inactivation, contrary to prolonged application of an agonist. It is noteworthy to point out that this effect is not mediated by conventional G-protein-coupling [ ], as it was demonstrated that this peptide's activity is contained within the 1—7 N-terminal fragment.
Intriguingly, some CGRP fragments quickly and reversibly enhance responses mediated by the activation of native neuronal nAChRs [ ]. The CGRP 1—6 peptide did not modify the muscle-type nicotinic receptor responses, indicating its selectivity for neuronal receptors.
This finding suggests that certain peptide derivatives shorter than CGRP 1—7 exert an unusual action, involving an apparently competitive modulation of the agonist-binding site. CGRP 1—6 and its derivatives may be used for the treatment of symptoms of neurological diseases associated with functional deficits of nAChRs and may be used as stem cell neuronal differentiation enhancers. Interestingly, nicotine has been shown to protect cells from apoptosis induced by anticancer drugs.
The acquisition of drug resistance is a considerable challenge in cancer therapy, and nAChR antagonists could be potentially used in combination with established chemotherapeutic drugs to enhance the therapeutic response to chemotherapy. The bioactivity of nAChR antagonists, however, has yet to be tested in animal models. Carefully designed animal studies are essential to investigate the potential side effects of nAChR antagonists on the brain, central nervous system, immune cells and muscle cells, all of which express high levels of nicotinic receptors.
The study of the roles of nAChRs in development and progression of cancer and stem cells differentiation provides novel opportunities for the prevention and therapy of cancer and degenerative disorders. However, it is important to consider that vital cell and organ functions are regulated by these receptors. However, experimental findings appear to be divergent and depend on the cell type and mode of administration used.
Among the calcium channel inhibitors, L- and T-type calcium blockers, were reported to inhibit neuronal differentiation [ 12 , — ], but have limited effect on other cell types. Mibefradil, a selective blocker of T-type channels, has significant anti-proliferative action in various cell types in vitro as well as in vivo [ , ].
The non-selective calcium blocker amlodipine is also a very effective protector of neuronal cells [ — ]. However, any attempt to prevent or treat cancer by targeting nAChRs must be based on the identification of molecular markers. The goal of this strategy is the restoration of balance between stimulatory and inhibitory signaling and not complete blockade of a given pathway.
Nicotinic signaling in non-neuronal cells has huge implications for cell fate and survival. Research in nAChR signaling networks will be especially relevant to stem cell production in a large scale and cancer treatment.
Future studies will need to define both the function of different nAChR subtypes in non-neuronal cells and the downstream signaling pathways that underlie the proliferative and anti-apoptotic activities of nicotine. Similarly to nicotinic signaling, the mechanisms that underlie the pro-mitogenic effects of muscarinic receptor stimulation have not yet been studied in detail.
However, several intracellular signaling pathways that regulate the synergistic mitogenic interaction of other GPCR agonists with growth factors in neural progenitor cells have been identified Figures 1 and 3.
This suggests that increases in intracellular calcium are essential, and may stimulate Pyk2 phosphorylation and then activate the MAPK signaling pathway [ ]. There is a growing body of evidence indicating that nicotinic and muscarinic receptors play important roles in stem cell differentiation and physiology. The disruption of developmental patterns and of normal function is often correlated with pathological conditions. Therefore, the controlled manipulation of ACh function may lead to novel therapies.
Strikingly, studies have revealed that drugs currently used to treat disorders such as Alzheimer's disease and depression, increase adult neurogenesis, which may be the mechanism mediating the activity of these drugs. However, some of these studies are controversial, and remain to be confirmed. Hence, the role of neurogenesis in treating central nervous system disorders, as well as the effects of drugs on embryonic and adult stem cells' neuronal differentiation remain areas of active research.
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