¹ Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao, China;

² Institute of Brain Science and Disorders, Qingdao University, Qingdao, China

Corresponding Author: Jie Wu, Professor, Institute of Brain Science and Disorders, Qingdao University, Room 509, Boya building, 308 Ningxia Rroad, Qingdao, 266071, China. E-mail: jiewu2@qdu.edu.cn.

Note: MengZhen Wang and Sha Zhao contributed equally.

	ABSTRACT
	INTRODUCTION
	INTRACELLULAR SECOND MESSENGER
	α7-nAChR AND INTRACELLULAR SECOND MESSENGER
	CONCLUSION
	AUTHOR CONTRIBUTIONS
	FUNDING
	CONFLICT OF INTERESTS
	ABBREVIATIONS
	REFERENCES

	ABSTRACT

Nicotinic acetylcholine receptors (nAChRs) are the members of the cys-loop ligandgated ion channel superfamily. They are cation-selective membrane proteins with a homopentameric or heteropentameric structure. The α7 subtype of nAChR (α7-nAChR) belongs to the classical homopentameric structure with the characteristics of relatively low affinity to agonists and high permeability to Ca²⁺. α7-nAChR plays an important role in modulating learning and memory, cognition, anti-inflammatory, growth and development, and other processes. There are many possible mechanisms underlying α7-nAChR-mediated modulations, including opening the high Ca²⁺ permeable channels, regulating presynaptic neurotransmitter release, and altering intracellular second messenger-mediated signaling pathways. Here, we summarize the signal pathways associated with α7-nAChR activation involving nucleotides, ions, lipids, and gas molecules. This article provides insights into α7-nAChR-mediated modulations through intracellular signaling systems and helps to understand the α7-nAChR-associated pathogenesis and therapeutics of a variety of diseases and disorders.

	INTRODUCTION

   Acetylcholine receptors

   There are two main types of acetylcholine receptors (AChRs): muscarinic acetylcholine receptors (mAChRs) and nicotinic acetylcholine receptors (nAChRs) (1). Both subtypes are activated by the endogenous neurotransmitter acetylcholine (ACh), and they are expressed in neurons and non-neuronal cells, participating in various physiological functions (2, 3) . mAChRs are typical G protein-coupled receptors, divided into five subtypes: M1-M5 (4). nAChRs are ligand-gated ion channels and the activation of nAChRs results in rapid cellular responses. Therefore, the application of nAChR agonists usually does not produce or produce only a barely detectable response in various tissues and organs (5).

   nAChR is a member of the cys-loop ligand-gated ion channel superfamily (1, 6) . They are cation-selective membrane proteins with a homopentameric or heteropentameric structure (7). The nAChRs are composed of different combinations of α (α2-α10) and β (β2-β4) subunits or α [7-9] subunit alone (8). The structure of nAChRs is consists of an extracellular domain, a transmembrane domain, and an intracellular domain. To date, more than 13 different neuronal nAChR subtypes have been discovered, including α1-α10, and β2-4 (1), each of which is closely related to a series of pathophysiological functions involving Parkinson's disease (PD), Alzheimer's disease (AD), and epilepsy, etc. (9-11) . In addition, α7-nAChR is associated with schizophrenia and AD (12) .

   In Goodman & Gilman's "The Pharmacological Basis of Therapeutics" (12th Edition, 2011), nAChR is classified into muscle type (Nm), peripheral neuron type (Nn), and central neuron type (CNS) based on the distribution, subunit composition, and selective antagonists. CNS nAChRs are expressed in neurons and glial cells in numerous brain regions. In its classification, the CNS nAChRs are further divided into two subtypes according to whether they are sensitive to α-bungarotoxin: (α4)2 (β2)3(insensitive) and (α7)5(sensitive). In all types of nAChRs, the opening of ion channels induced by agonists (such as ACh or nicotine) binding causes Na+ and Ca²⁺ influx. This depolarizes the cells and opens various function switches (1). Detecting postsynaptic nicotine responses of neurons in the central nervous system is relatively complicated, as most neuronal nAChRs rapidly desensitize when exposed to nicotine agonists (1, 13) .

   α7 nicotinic acetylcholine receptors

   The neuronal type α7-nAChR is a homopentamer, meaning that it consists of five identical subunits. α7-nAChRs are highly expressed in the central nervous system (cortex, striatum, and hippocampus) in the human brain (14) . They play an important role in advanced neural functions (such as cognitive function, learning, and memory processes) and cholinergic anti-inflammatory pathways (15-17) . Emerging evidence suggests that the altered α7-nAChR subtype is related to the pathogenesis of AD (18) .

   Natural α7-nAChRs are expressed on both presynaptic and postsynaptic membranes, and they act as the regulators of circuit activity in the brain (8, 19) . Although α7-nAChRs are desensitized in the sub-millisecond range, its relatively high Ca²⁺ permeability exhibits physiological significance (20) . In fact, selective activation of α7-nAChRs indicates that they improve the learning and memory, and anxiety conditions (21, 22) . On the other hand, deficits of α7-nAChR function are associated with various diseases including AD, schizophrenia and pain (23, 24) . However, accumulating lines of evidence suggest that up-regulation of α7-nAChRs may produce neurotoxic effects and damage neurons (25-27) . These lines of evidence suggest that the α7-nAChR-mediated modulations may involve complicated mechanisms and signal pathways.

	INTRACELLULAR SECOND MESSENGER

   The second messengers are a series of small molecules and ions that respond to the first messenger outside the cell and transmit the signal received by the cell surface receptor to the effector protein (28, 29) . Its synthesis and degradation are controlled by a variety of enzymes in mammalian cells (28). Since the discovery that cyclic adenosine monophosphate (cAMP) (the first found second messenger) plays a role in the signal transduction process (30), more small molecules and ions have been found to also play a similar role, and have different nature, allowing them to carry information within the membrane (hydrophobic molecules, such as lipids and lipid derivatives), in the cytoplasm (polar molecules, such as nucleotides and ions), or between the two (such as gases and free radicals) transfer (29, 31) . Second messengers not only respond to extracellular stimuli, but also respond to intracellular stimuli. They usually are available in resting cells at lower concentrations and can be produced or released quickly when cells are stimulated (29). The concentration level of second messengers is precisely regulated by diverse mechanisms. In the process of information transmission, enzymatic reactions or the opening of ion channels ensure that they are highly amplified to improve the accuracy of cell signal transduction (32) . There are only a few known second messengers, but they can transmit a variety of extracellular information, cause-specific intracellular reactions, and thereby regulate different physiological and biochemical processes (31).

	a7-nAChR AND INTRACELLULAR SECOND MESSENGER

   α7-nAChR and cAMP

   Adenylate cyclase (AC) convert adenosine triphosphate (ATP) into cAMP and pyrophosphate. AC can be divided into three families: calcium ion and calmodulin activated type (AC1, AC3, and AC8), Ca²⁺ inhibited type (AC5, AC6, and AC9) and Ca²⁺ insensitive type (AC2, AC4, and AC7) (33) .

   It is well known that the activation of AC can increase the release of glutamate from hippocampal neurons (34) . For a long time, cAMP has been recognized as a gated molecule that controls the expression of short-term plasticity and its transformation into long-term plasticity (35, 36) . Cheng et al. (2011) investigated the relationship between cAMP and α7-nAChR-mediated signal transduction mechanism in cultured mouse hippocampal neurons and found that activation of α7-nAChRs resulted in an increased intracellular cAMP level, which depended on the increase of cytoplasmic calcium and calcium-stimulated AC1 activations (37) . It has been reported that the use of selective AC1 inhibitors or siRNA to inhibit AC1 can prevent α7-nAChR-mediated cAMP elevation, which indicates that calcium-dependent AC1 can convert short-term calcium elevation into cAMP signal when α7-nAChR is activated, and then lead to a series of cascading reactions (38) .

   The activation of α7-nAChRs induced the prolongation and enhancement of glutamatergic synaptic transmission in a PKA-dependent manner (39) . In the presence of α7-nAChR positive allosteric modulator PNU-120596, treatment with α7-nAChR selective agonist choline can increase intracellular cAMP levels. This increase in cAMP induced by choline was eliminated by the α7-nAChR antagonist methyllycaconitine (MLA) and the calcium chelator BAPTA, indicating that the increase of cAMP depends on the activation of α7-nAChRs and the subsequent increase in intracellular calcium. Both the selective AC1 inhibitor CB-6673567 and siRNA-mediated AC1 deletion prevented the increase in cAMP brought about by choline, indicating that the effect of choline requires calcium-dependent AC1 (37, 38) .

   In addition, in the hippocampus, calcium-stimulated presynaptic terminal AC-dependent PKA activation is mainly driven by AC1 rather than AC8 (40) . There is evidence that the activity of PKA is necessary for α7-nAChR-mediated enhancement of evoked excitatory post-synaptic current (eEPSC) amplitude. Previous studies have shown that PKA can regulate synaptic plasticity of the entire hippocampus, especially at the ends of mossy fibers (41-45) . Besides, inhibition of PKA activity can block the α7-nAChR-mediated effect on hippocampal synaptic plasticity (46) . It can be seen that under the stimulation of calcium and calmodulin, AC1 is a suitable candidate for coupling α7-nAChR with PKA (37, 39) .

   To sum up, α7-nAChRs use the AC1-cAMP-PKA signal transduction pathway to phosphorylate synaptic proteins, and the synaptic proteins act as downstream effectors that regulate neurotransmitter release, thereby mediating its regulation of synaptic transmission and positive effects on cognition (37) .

   α7-nAChR and Ca²⁺

   It is well known that Ca²⁺ is an important signal transduction molecule in neuronal cells (47) . Many studies have also shown that α7-nAChR-mediated effects are mediated by the activation of intracellular Ca²⁺ signals, which reveals the physiological roles of receptor channels (48) .

   Ca²⁺-AC1-cAMP-PKA/PKC. It has been reported that in cystic fibrosis disease (CF), loss or dysfunction of the transmembrane conductance regulator (CFTR) leads to an impaired airway mucus transport. The α7-nAChR is a key regulator of CFTR functional activity in airway epithelial cells of surface epithelium and submucosal glands, and the two are functionally coupled through Ca²⁺: Activation of α7-nAChR leads to Ca²⁺ influx, which leads to AC1 activation and cAMP production, which in turn initiates a series of PKA/PKC cascades, eventually leading to CFTR Cl- channel outflow of Cl-, and maintaining normal airway epithelium homeostasis (49, 50) .

   Ca²⁺/CaM-eNOS-NO. There is evidence that a variety of neuromodulators are involved in the cardiovascular control of nucleus tractus solitarii (NTS), of which nicotine plays a key role in central cardiovascular control (51, 52) . eNOS is a constitutive and strictly Ca²⁺/calmodulin(CaM)-dependent enzyme. When the intracellular calcium concentration increases, calmodulin will replace caveolin, and act by stimulating phosphorylation of serine 1177 of eNOS (53) . Previous experiments have found that microinjection of nicotine into the NTS of Wistar-Kyoto rats (WKY rats) can cause a dose-dependent decrease in blood pressure (BP) and heart rate (HR), which indicates that nAChRs play an important role in the BP control of NTS. After pretreatment with nAChR antagonists or calmodulin-eNOS pathway blockers, this inhibitory effect of nicotine was weakened. In contrast, treatment with nNOS-specific inhibitors did not attenuate the nicotine-mediated effects. This indicates that eNOS may be one of the downstream targets of nAChRs, and regulate the BP in NTS of WKY rats by participating in the production of NO. And after nicotine was injected into NTS, it was found that calmodulin can bind to eNOS (47) . In short, the antihypertensive effect of nAChR regulation in NTS is achieved through the production of NO induced by eNOS, and the regulation of eNOS activity is achieved through the combination with Ca²⁺/CaM, that is, α7-nAChR-Ca²⁺/CaM-eNOS-NO pathway may play a role in the regulation of BP in NTS.

   Ca²⁺–CaMKII–PKC. Acetylcholine concentrations in corneal epithelium are very high (54) , even exceeding the concentrations in nerve tissue (55) . ACh axis plays an important role in regulating and coordinating the different activities of corneal epithelial cells mediated re-epithelialization (56) . It was found that autocrine/paracrine ACh and cholinergic agonists could up-regulate the expression of E-cadherin by activating α7-nAChR, thus promoting corneal epithelial regeneration. Activation of α7-nAChRs can indirectly initiate the Ras–Raf–MEK–ERK cascade through the Ca²⁺–CaMKII–PKC signal pathway, or it can directly interact with Ras (57) .

   Ca²⁺–CaM-CaMKII-CREB. AD is the most common type of neurodegenerative diseases, and there are multiple pathogenesis hypotheses, among which amyloid β protein(Aβ) deposition plays an important role in the pathogenesis of AD (18, 58-60) . Aβ deposition in the brain can lead to the imbalance of neuronal calcium homeostasis and decline in cognitive function (61) . nAChRs are involved in various important physiological processes, especially in learning, memory, and cognition, and α7-nAChRs is one of the subtypes of nAChR related to the pathogenesis of AD (18) . Also, studies have found that in different AD models, the use of α7-nAChRs-specific agonists can improve cognitive impairment (62) .

   Studies have shown that cognitive decline in AD patients is closely related to impaired synaptic function (63). Synapses are the basic structure of connections between neurons, play a key role in information transmission, and are the foundation of learning and memory. The function of synapses is largely related to synapse-related proteins (18) . It has been found that the activation of α7-nAChRs by PNU-282987 (α7-nAChR specific agonist) can restore the expression levels of synapse-related proteins down-regulated due to Aβ deposition, including SYN, PSD95, SNAP25, DYN1, and AP180. When the α7-nAChR antagonist MLA was used to treat primary hippocampal neurons, the expression of the synapse-related protein decreased. As an intracellular second messenger, Ca²⁺ can get into the cell through α7-nAChRs and combine with CaM to form an active CaM complex. The CaM complex can bind to CaMKII, change the spatial conformation of CaMKII and phosphorylate it. Phosphorylated CaMKII enters the nucleus to catalyze the phosphorylation of CREB. CREB is located in the downstream of the α7-nAChR signal transduction pathway, and acts as a transcription factor to regulate the growth and development of neurons and the formation of long-term memory, thereby exerting neuroprotective effects (18, 64, 65) .

   Changes in Ca²⁺ homeostasis in AD patients are related to synaptic dysfunction and neuronal decline (66) . PNU-282987 activates α7-nAChRs in both in vivo and in vitro models, thereby activating CaM-CaMKII-CREB signaling pathway to maintain intracellular Ca²⁺ steady state (18, 66) . This may provide a new understanding of the underlying pathogenesis of AD.

   α7-nAChR and IP3

   Nicotine activation of presynaptic nAChRs can promote neurotransmitter release and produce short-term and long-term enhancement effects on synaptic plasticity (67, 68) . Regulating the entry of Ca²⁺ at the presynaptic terminal is an important step to determine the degree of neurotransmitter release (69) . The nAChRs-mediated Ca²⁺ influx and subsequent Ca²⁺-dependent signal stimulation may be involved in the continuous phase of nicotine-induced synaptic transmission (67) . The activation of nAChRs can induce Ca²⁺ influx through direct penetration of receptor channels and activation of voltage-gated Ca²⁺ channels. Activation of α7-nAChR (high Ca²⁺ permeability) causes an increase in Ca²⁺ at the presynaptic terminal, which is sufficient to induce the release of calcium from the IP3-sensitive Ca²⁺ pool and maintain continuous changes in intracellular Ca²⁺ (69) . Activation of α7-nAChR can also activate phospholipase C (PLC) through a certain mechanism. PLC decomposes PIP2 to generate IP3, thereby mobilizing IP3 receptors to regulate calcium storage (70, 71) . CaMKII is activated by the activation of α7nAChR, and the activated CaMKII maintains the increase of presynaptic Ca²⁺ through a positive feedback mechanism. Activated CaMKII is related to presynaptic neurotransmitter vesicles and participates in the regulation of neurotransmitter release and synaptic transmission (72, 73) . The continuous changes of intracellular Ca²⁺ and the activation of CaMKII at the presynaptic terminal trigger the long-term enhancement of glutamate release and induce long-term promotion of glutamatergic synaptic transmission (69) .

   After nicotine activates α7-nAChR, through the α7-nAChR-PLC-IP3-CaMKII cascade, or α7-nAChR directly interacts with Ca²⁺, both can trigger the release of presynaptic glutamate, which ultimately acts on the postsynaptic region, causing a series of physiological and biochemical reactions.

   In addition, α7-nAChRs are also involved in signal transduction processes such as the activation of PLC and the release of intracellular Ca²⁺ in microglia, rather than acting as a traditional ion channel (70, 74) . This α7-nAChR signal transmission may be involved in the functional activation process of nicotine on microglia, exerting neuroprotective effects by inhibiting the inflammatory state and enhancing the protective function (70) .

   α7-nAChR and NO

   During the mutual regulation of nicotine and ethanol, nAChR acts as an intermediate target (75) . The cross-tolerance between nicotine and ethanol is dependent on the nAChR (76-78) . However, it is worth noting that α7-selective agonists can attenuate ethanol-induced ataxia, and this effect was partially block by α7-selective antagonists, which indicates that this process may be mediated by α7-nAChRs (78) . Pretreatment with RJR-2403 (α4β2nAChR selective agonist) or PNU-282987 (α7-nAChR selective agonist) can reverse the reduction of NOx (total nitrate + nitrite) caused by ethanol. The change of NOx level indicates that the NO-cGMP signaling pathway may be a mechanism of α4β2 and α7-nAChR subtypes mediated cross tolerance between nicotine and ethanol (75, 79) .

   In short, α7-nAChR may participate in the interaction between nicotine and ethanol through the NO-cGMP signaling pathway, thereby reducing the ataxia caused by ethanol (78) .

	CONCLUSION

   α7-nAChR is not only distributed in the central nervous system and peripheral nervous system, but also in the immune system. In recent years, there are more and more studies on the physiological or pathological roles of α7-nAChR. The wide distribution of α7-nAChR makes it a target for the treatment of neurodegenerative diseases and other diseases. Its agonists and positive allosteric modulators have also become the hot spots of drug research and development. We summarized that α7-nAChR can play a role through several intracellular second messengers and subsequent cascades (Table 1). We also found that the relationship between these signal cascades is complex (Figure 1). Further exploringe these signal networks, to understand the mechanisms and functions of α7-nAChR should be our focus.

View larger version : [in a new window] Figure 1. Schematic diagram of α7-nAChR signaling pathway.

	AUTHOR CONTRIBUTIONS

   Jie Wu designed the outline study, analyzed information, and contributed to manuscript writing; Mengzhen Wang conducted the literature search and selection, then wrote the manuscript; Sha Zhao was responsible for summarizing tables and figures in articles; Yudan Zhang and Wei Liu contributed to study design. All of the authors have read and approved the final manuscript.

	FUNDING

   This work was supported by the Key Area Research and Development Program of Guangdong Province (2018B030334001).

	CONFLICT OF INTERESTS

   The authors declare that no conflicting interests exist.

	ABBREVIATIONS

Aβ	amyloid β protein
AC	adenylate cyclase
Ach	acetylcholine
AChR	acetylcholine receptors
AD	alzheimer’s disease
ATP	adenosine triphosphate
BP	blood pressure
CaM	calmodulin
cAMP	cyclic adenosine monophosphate
CF	fibrosis disease
eEPSC	evoked excitatory post-synaptic current
HR	heart rate
mAChR	muscarinic acetylcholine receptors
MLA	methyllycaconitine
nAChR	nicotinic acetylcholine receptors
NTS	nucleus tractus solitarii
PD	parkinson’s disease
PLC	phospholipase C

	REFERENCES

1. Albuquerque EX, Pereira EF, Alkondon M, Rogers SW. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev. 2009; 89 (1): 73-120.
2. Dani JA, Bertrand D. Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol. 2007; 47: 699-729.
3. Cobb SR, Davies CH. Cholinergic modulation of hippocampal cells and circuits. J Physiol. 2005; 562 (Pt 1): 81-88.
4. Caulfield MP, Birdsall NJ. International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev. 1998; 50 (2): 279-290.
5. McQuiston AR, Madison DV. Nicotinic receptor activation excites distinct subtypes of interneurons in the rat hippocampus. J Neurosci. 1999; 19 (8): 2887-2896.
6. Faghih R, Gfesser GA, Gopalakrishnan M. Advances in the discovery of novel positive allosteric modulators of the alpha7 nicotinic acetylcholine receptor. Recent Pat CNS Drug Discov. 2007; 2 (2): 99-106.
7. Pesti K, Lukacs P, Mike A. Type I-like behavior of the type II alpha7 nicotinic acetylcholine receptor positive allosteric modulator A-867744. Peer J. 2019; 7: e7542.
8. Gotti C, Zoli M, Clementi F. Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Trends Pharmacol Sci. 2006; 27 (9): 482-491.
9. Isaias IU, Spiegel J, Brumberg J, Cosgrove KP, et al. Nicotinic acetylcholine receptor density in cognitively intact subjects at an early stage of Parkinson's disease. Front Aging Neurosci. 2014; 6: 213.
10. Lombardo S, Maskos U. Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment. Neuropharmacology. 2015; 96 (Pt B): 255-262.
11. Becchetti A, Aracri P, Meneghini S, Brusco S, et al. The role of nicotinic acetylcholine receptors in autosomal dominant nocturnal frontal lobe epilepsy. Front Physiol. 2015; 6: 22.
12. Brumwell CL, Johnson JL, Jacob MH. Extrasynaptic alpha 7-nicotinic acetylcholine receptor expression in developing neurons is regulated by inputs, targets, and activity. J Neurosci. 2002; 22 (18): 8101-8109.
13. Frazier CJ, Buhler AV, Weiner JL, Dunwiddie TV. Synaptic potentials mediated via alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in rat hippocampal interneurons. J Neurosci. 1998; 18 (20): 8228-8235.
14. Zoli M, Pistillo F, Gotti C. Diversity of native nicotinic receptor subtypes in mammalian brain. Neuropharmacology. 2015; 96 (Pt B): 302-311.
15. Thomsen MS, Hansen HH, Timmerman DB, Mikkelsen JD. Cognitive improvement by activation of alpha7 nicotinic acetylcholine receptors: from animal models to human pathophysiology. Curr Pharm Des. 2010; 16 (3): 323-343.
16. Kalkman HO, Feuerbach D. Modulatory effects of alpha7 nAChRs on the immune system and its relevance for CNS disorders. Cell Mol Life Sci. 2016; 73 (13): 2511-2530.
17. Pavlov VA, Wang H, Czura CJ, Friedman SG, et al. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med. 2003; 9 (5-8): 125-134.
18. Wang XL, Deng YX, Gao YM, Dong YT, et al. Activation of α7 nAChR by PNU-282987 improves synaptic and cognitive functions through restoring the expression of synaptic-associated proteins and the CaM-CaMKII-CREB signaling pathway. Aging (Albany NY). 2020; 12 (1): 543-570.
19. Miwa JM, Freedman R, Lester HA. Neural systems governed by nicotinic acetylcholine receptors: emerging hypotheses. Neuron. 2011; 70 (1): 20-33.
20. Dawe GB, Yu H, Gu S, Blackler AN, et al. alpha7 nicotinic acetylcholine receptor upregulation by anti-apoptotic Bcl-2 proteins. Nat Commun. 2019; 10 (1): 2746.
21. Picciotto MR, Caldarone BJ, Brunzell DH, Zachariou V, et al. Neuronal nicotinic acetylcholine receptor subunit knockout mice: physiological and behavioral phenotypes and possible clinical implications. Pharmacol Ther. 2001; 92 (2-3): 89-108.
22. Pandya AA, Yakel JL. Effects of neuronal nicotinic acetylcholine receptor allosteric modulators in animal behavior studies. Biochem Pharmacol. 2013; 86 (8): 1054-1062.
23. Dineley KT, Pandya AA, Yakel JL. Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol Sci. 2015; 36 (2): 96-108.
24. Bertrand D, Lee CH, Flood D, Marger F, et al. Therapeutic Potential of alpha7 Nicotinic Acetylcholine Receptors. Pharmacol Rev. 2015; 67 (4): 1025-1073.
25. Liu Q, Xie X, Lukas RJ, St John PA, et al. A novel nicotinic mechanism underlies β-amyloid-induced neuronal hyperexcitation. J Neurosci. 2013; 33 (17): 7253-7263.
26. Liu Q, Xie X, Emadi S, Sierks MR, et al. A novel nicotinic mechanism underlies β-amyloid-induced neurotoxicity. Neuropharmacology. 2015; 97: 457-463.
27. Dziewczapolski G, Glogowski CM, Masliah E, Heinemann SF. Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease. J Neurosci. 2009; 29 (27): 8805-8815.
28. Bornfeldt KE. A single second messenger: several possible cellular responses depending on distinct subcellular pools. Circ Res. 2006; 99 (8): 790-792.
29. Newton AC, Bootman MD, Scott JD. Second Messengers. Cold Spring Harb Perspect Biol. 2016; 8 (8).
30. Sutherland EW, Robison GA. The role of cyclic-3',5'-AMP in responses to catecholamines and other hormones. Pharmacol Rev. 1966; 18 (1): 145-161.
31. Stangherlin A, O'Neill JS. Signal Transduction: Magnesium Manifests as a Second Messenger. Curr Biol. 2018; 28 (24): R1403-r1405.
32. Heldin CH, Lu B, Evans R, Gutkind JS. Signals and Receptors. Cold Spring Harb Perspect Biol. 2016; 8 (4): a005900.
33. Alexander SP, Fabbro D, Kelly E, Marrion NV, et al. THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Enzymes. Br J Pharmacol. 2017; 174 Suppl 1: S272-S359.
34. Moulder KL, Jiang X, Chang C, Taylor AA, et al. A specific role for Ca²⁺-dependent adenylyl cyclases in recovery from adaptive presynaptic silencing. J Neurosci. 2008; 28 (20): 5159-5168.
35. Kandel ER. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain. 2012; 5: 14.
36. Kandel ER, Dudai Y, Mayford MR. The molecular and systems biology of memory. Cell. 2014; 157 (1): 163-186.
37. Cheng Q, Yakel JL. Activation of alpha7 nicotinic acetylcholine receptors increases intracellular cAMP levels via activation of AC1 in hippocampal neurons. Neuropharmacology. 2015; 95: 405-414.
38. Gu Z, Yakel JL. Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity. Neuron. 2011; 71 (1): 155-165.
39. Cheng Q, Yakel JL. Presynaptic alpha7 nicotinic acetylcholine receptors enhance hippocampal mossy fiber glutamatergic transmission via PKA activation. J Neurosci. 2014; 34 (1): 124-133.
40. Conti AC, Maas JW Jr., Moulder KL, Jiang X, et al. Adenylyl cyclases 1 and 8 initiate a presynaptic homeostatic response to ethanol treatment. PLoS One. 2009; 4 (5): e5697.
41. Pelkey KA, Topolnik L, Yuan XQ, Lacaille JC, et al. State-dependent cAMP sensitivity of presynaptic function underlies metaplasticity in a hippocampal feedforward inhibitory circuit. Neuron. 2008; 60 (6): 980-987.
42. Wozny C, Maier N, Fidzinski P, Breustedt J, et al. Differential cAMP signaling at hippocampal output synapses. J Neurosci. 2008; 28 (53): 14358-14362.
43. Caiati MD, Safiulina VF, Fattorini G, Sivakumaran S, et al. PrPC controls via protein kinase A the direction of synaptic plasticity in the immature hippocampus. J Neurosci. 2013; 33 (7): 2973-2983.
44. Nicoll RA, Schmitz D. Synaptic plasticity at hippocampal mossy fibre synapses. Nat Rev Neurosci. 2005; 6 (11): 863-876.
45. Rodriguez-Moreno A, Sihra TS. Metabotropic actions of kainate receptors in the control of glutamate release in the hippocampus. Adv Exp Med Biol. 2011; 717: 39-48.
46. Welsby PJ, Rowan MJ, Anwyl R. Intracellular mechanisms underlying the nicotinic enhancement of LTP in the rat dentate gyrus. Eur J Neurosci. 2009; 29 (1): 65-75.
47. Cheng PW, Lu PJ, Chen SR, Ho WY, et al. Central nicotinic acetylcholine receptor involved in Ca(2+) -calmodulin-endothelial nitric oxide synthase pathway modulated hypotensive effects. Br J Pharmacol. 2011; 163 (6): 1203-1213.
48. Gilbert D, Lecchi M, Arnaudeau S, Bertrand D, Demaurex N. Local and global calcium signals associated with the opening of neuronal alpha7 nicotinic acetylcholine receptors. Cell Calcium. 2009; 45 (2): 198-207.
49. Hollenhorst MI, Lips KS, Weitz A, Krasteva G, et al. Evidence for functional atypical nicotinic receptors that activate K+-dependent Cl- secretion in mouse tracheal epithelium. Am J Respir Cell Mol Biol. 2012; 46 (1): 106-114.
50. Maouche K, Medjber K, Zahm JM, Delavoie F, et al. Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure. Proc Natl Acad Sci U S A. 2013; 110 (10): 4099-4104.
51. Tseng CJ, Appalsamy M, Robertson D, Mosqueda-Garcia R. Effects of nicotine on brain stem mechanisms of cardiovascular control. J Pharmacol Exp Ther. 1993; 265 (3): 1511-1518.
52. Tseng CJ, Ger LP, Lin HC, Tung CS. The pressor effect of nicotine in the rostral ventrolateral medulla of rats. Chin J Physiol. 1994; 37 (2): 83-87.
53. Fleming I, Fisslthaler B, Dimmeler S, Kemp BE, et al. Phosphorylation of Thr(495) regulates Ca(2+)/calmodulin-dependent endothelial nitric oxide synthase activity. Circ Res. 2001; 88 (11): E68-75.
54. Klapproth H, Reinheimer T, Metzen J, Münch M, et al. Non-neuronal acetylcholine, a signalling molecule synthezised by surface cells of rat and man. Naunyn Schmiedebergs Arch Pharmacol. 1997; 355 (4): 515-523.
55. Stevenson RW, Wilson WS. Drug-induced depletion of acetylcholine in the rabbit corneal epithelium. Biochem Pharmacol. 1974; 23 (24): 3449-3457.
56. Chernyavsky AI, Galitovskiy V, Shchepotin IB, Jester JV, et al. The acetylcholine signaling network of corneal epithelium and its role in regulation of random and directional migration of corneal epithelial cells. Invest Ophthalmol Vis Sci. 2014; 55 (10): 6921-6933.
57. Chernyavsky AI, Galitovskiy V, Grando SA. Molecular mechanisms of synergy of corneal muscarinic and nicotinic acetylcholine receptors in upregulation of E-cadherin expression. Int Immunopharmacol. 2015; 29 (1): 15-20.
58. Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 2014; 71 (4): 505-508.
59. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011; 10 (9): 698-712.
60. Flores J, Noël A, Foveau B, Lynham J, et al. Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model. Nat Commun. 2018; 9 (1): 3916.
61. Jagust W. Is amyloid-β harmful to the brain? Insights from human imaging studies. Brain. 2016; 139 (Pt 1): 23-30.
62. Marcus MM, Björkholm C, Malmerfelt A, Möller A, et al. Alpha7 nicotinic acetylcholine receptor agonists and PAMs as adjunctive treatment in schizophrenia. An experimental study. Eur Neuropsychopharmacol. 2016; 26 (9): 1401-1411.
63. Bressloff PC, Earnshaw BA. A dynamic corral model of receptor trafficking at a synapse. Biophys J. 2009; 96 (5): 1786-1802.
64. Bitner RS, Bunnelle WH, Anderson DJ, Briggs CA, et al. Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways. J Neurosci. 2007; 27 (39): 10578-10587.
65. Medeiros R, Castello NA, Cheng D, Kitazawa M, et al. α7 Nicotinic receptor agonist enhances cognition in aged 3xTg-AD mice with robust plaques and tangles. Am J Pathol. 2014; 184 (2): 520-529.
66. Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007; 8 (2): 101-112.
67. Zhong C, Du C, Hancock M, Mertz M, et al. Presynaptic type III neuregulin 1 is required for sustained enhancement of hippocampal transmission by nicotine and for axonal targeting of alpha7 nicotinic acetylcholine receptors. J Neurosci. 2008; 28 (37): 9111-9116.
68. Mao D, Gallagher K, McGehee DS. Nicotine potentiation of excitatory inputs to ventral tegmental area dopamine neurons. J Neurosci. 2011; 31 (18): 6710-6720.
69. Zhong C, Talmage DA, Role LW. Nicotine elicits prolonged calcium signaling along ventral hippocampal axons. PLoS One. 2013; 8 (12): e82719.
70. Suzuki T, Hide I, Matsubara A, Hama C, et al. Microglial alpha7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role. J Neurosci Res. 2006; 83 (8): 1461-1470.
71. Razani-Boroujerdi S, Boyd RT, Dávila-García MI, Nandi JS, et al. T cells express alpha7-nicotinic acetylcholine receptor subunits that require a functional TCR and leukocyte-specific protein tyrosine kinase for nicotine-induced Ca²⁺ response. J Immunol. 2007; 179 (5): 2889-2898.
72. Salin PA, Scanziani M, Malenka RC, Nicoll RA. Distinct short-term plasticity at two excitatory synapses in the hippocampus. Proc Natl Acad Sci U S A. 1996; 93 (23): 13304-13309.
73. Wang BW, Liao WN, Chang CT, Wang SJ. Facilitation of glutamate release by nicotine involves the activation of a Ca²⁺/calmodulin signaling pathway in rat prefrontal cortex nerve terminals. Synapse. 2006; 59 (8): 491-501.
74. Takahashi T, Yoshida T, Harada K, Miyagi T, et al. Component of nicotine-induced intracellular calcium elevation mediated through α3- and α5-containing nicotinic acetylcholine receptors are regulated by cyclic AMP in SH-SY 5Y cells. PLoS One. 2020; 15 (11): e0242349.
75. Marszalec W, Aistrup GL, Narahashi T. Ethanol-nicotine interactions at alpha-bungarotoxin-insensitive nicotinic acetylcholine receptors in rat cortical neurons. Alcohol Clin Exp Res. 1999; 23 (3): 439-445.
76. Al-Rejaie S, Dar MS. Possible role of mouse cerebellar nitric oxide in the behavioral interaction between chronic intracerebellar nicotine and acute ethanol administration: observation of cross-tolerance. Neuroscience. 2006; 138 (2): 575-585.
77. Taslim N, Al-Rejaie S, Saeed Dar M. Attenuation of ethanol-induced ataxia by alpha(4)beta(2) nicotinic acetylcholine receptor subtype in mouse cerebellum: a functional interaction. Neuroscience. 2008; 157 (1): 204-213.
78. Taslim N, Soderstrom K, Dar MS. Role of mouse cerebellar nicotinic acetylcholine receptor (nAChR) α(4)β(2)- and α(7) subtypes in the behavioral cross-tolerance between nicotine and ethanol-induced ataxia. Behav Brain Res. 2011; 217 (2): 282-292.
79. Al-Rejaie S, Dar MS. Antagonism of ethanol ataxia by intracerebellar nicotine: possible modulation by mouse cerebellar nitric oxide and cGMP. Brain Res Bull. 2006; 69 (2): 187-196.

The exquisite patterns on the luxury replica watches dial, the date display window at replica watches six o'clock, and the black sculpted Arabic numerals demonstrate the replica rolex exquisite craftsmanship of rolex watches uk the fine watchmaking style.