Abstract
Nicotinic acetylcholine receptors (nAChRs) have gained much attention in the scientific community since they play a significant role in multiple physiological and pathophysiological processes. Multiple approaches to study the receptors exist, with characterization of the receptors’ functionality at a single cellular level using cell culturing being one of them. Derived from an adrenal medulla tumor, PC12 cells express nicotinic receptor subunits and form functional nicotinic receptors. Thus, the cells offer a convenient environment to address questions related to the functionality of the receptors. The review summarizes the findings on nicotinic receptors’ expression and functions which were conducted using PC12 cells. Specific focus is given to α3-containing receptors as well as α7 receptor. Critical evaluation of findings is provided alongside insights into what can still be learned about nAChRs, using PC12 cells.
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References
Albillos A, McIntosh JM (2018) Human nicotinic receptors in chromaffin cells: characterization and pharmacology. Pflugers Arch 470:21–27. https://doi.org/10.1007/s00424-017-2073-0
Amy CM, Bennett EL (1983) Increased sodium ion conductance through nicotinic acetylcholine receptor channels in PC12 cells exposed to nerve growth factors. J Neurosci 3:1547–1553
Arredondo J et al (2002) Central role of alpha7 nicotinic receptor in differentiation of the stratified squamous epithelium. J Cell Biol 159:325–336. https://doi.org/10.1083/jcb.200206096
Ballinger EC, Ananth M, Talmage DA, Role LW (2016) Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline. Neuron 91:1199–1218. https://doi.org/10.1016/j.neuron.2016.09.006
Bartus RT, Dean RL 3rd, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414. https://doi.org/10.1126/science.7046051
Beckmann J, Lips KS (2013) The non-neuronal cholinergic system in health and disease. Pharmacology 92:286–302. https://doi.org/10.1159/000355835
Bloem B, Poorthuis RB, Mansvelder HD (2014) Cholinergic modulation of the medial prefrontal cortex: the role of nicotinic receptors in attention and regulation of neuronal activity. Front Neural Circuits 8:17. https://doi.org/10.3389/fncir.2014.00017
Blumenthal EM, Conroy WG, Romano SJ, Kassner PD, Berg DK (1997) Detection of functional nicotinic receptors blocked by alpha-bungarotoxin on PC12 cells and dependence of their expression on post-translational events. J Neurosci 17:6094–6104
Boccia MM, Blake MG, Krawczyk MC, Baratti CM (2010) Hippocampal alpha7 nicotinic receptors modulate memory reconsolidation of an inhibitory avoidance task in mice. Neuroscience 171:531–543. https://doi.org/10.1016/j.neuroscience.2010.08.027
Bohnen NI, Albin RL (2011) The cholinergic system and Parkinson disease. Behav Brain Res 221:564–573. https://doi.org/10.1016/j.bbr.2009.12.048
Boulter J, Evans K, Goldman D, Martin G, Treco D, Heinemann S, Patrick J (1986) Isolation of a cDNA clone coding for a possible neural nicotinic acetylcholine receptor alpha-subunit. Nature 319:368–374. https://doi.org/10.1038/319368a0
Boulter J et al (1990) Alpha 3, alpha 5, and beta 4: three members of the rat neuronal nicotinic acetylcholine receptor-related gene family form a gene cluster. J Biol Chem 265:4472–4482
Campos-Caro A et al (1997) Neuronal nicotinic acetylcholine receptors on bovine chromaffin cells: cloning, expression, and genomic organization of receptor subunits. J Neurochem 68:488–497
Campos-Caro A, Carrasco-Serrano C, Valor LM, Viniegra S, Ballesta JJ, Criado M (1999) Multiple functional Sp1 domains in the minimal promoter region of the neuronal nicotinic receptor alpha5 subunit gene. J Biol Chem 274:4693–4701
Cartier GE, Yoshikami D, Gray WR, Luo S, Olivera BM, McIntosh JM (1996) A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors. J Biol Chem 271:7522–7528
Chan J, Quik M (1993) A role for the nicotinic alpha-bungarotoxin receptor in neurite outgrowth in PC12 cells. Neuroscience 56:441–451
Chen CS et al (2011) Nicotine-induced human breast cancer cell proliferation attenuated by garcinol through down-regulation of the nicotinic receptor and cyclin D3 proteins. Breast Cancer Res Treat 125:73–87. https://doi.org/10.1007/s10549-010-0821-3
Chernyavsky AI, Arredondo J, Vetter DE, Grando SA (2007) Central role of alpha9 acetylcholine receptor in coordinating keratinocyte adhesion and motility at the initiation of epithelialization. Exp Cell Res 313:3542–3555. https://doi.org/10.1016/j.yexcr.2007.07.011
Colomer C, Olivos-Ore LA, Vincent A, McIntosh JM, Artalejo AR, Guerineau NC (2010) Functional characterization of alpha9-containing cholinergic nicotinic receptors in the rat adrenal medulla: implication in stress-induced functional plasticity. J Neurosci 30:6732–6742. https://doi.org/10.1523/JNEUROSCI.4997-09.2010
Conti V et al (2015) Nocturnal frontal lobe epilepsy with paroxysmal arousals due to CHRNA2 loss of function. Neurology 84:1520–1528. https://doi.org/10.1212/WNL.0000000000001471
Criado M (2018) Acetylcholine nicotinic receptor subtypes in chromaffin cells. Pflugers Arch 470:13–20. https://doi.org/10.1007/s00424-017-2050-7
Criado M, Valor LM, Mulet J, Gerber S, Sala S, Sala F (2012) Expression and functional properties of alpha7 acetylcholine nicotinic receptors are modified in the presence of other receptor subunits. J Neurochem 123:504–514. https://doi.org/10.1111/j.1471-4159.2012.07931.x
Cui C et al (2003) The beta3 nicotinic receptor subunit: a component of alpha-conotoxin MII-binding nicotinic acetylcholine receptors that modulate dopamine release and related behaviors. J Neurosci 23:11045–11053
Dajas-Bailador F, Wonnacott S (2004) Nicotinic acetylcholine receptors and the regulation of neuronal signalling. Trends Pharmacol Sci 25:317–324. https://doi.org/10.1016/j.tips.2004.04.006
Dash B, Lukas RJ, Li MD (2014) A signal peptide missense mutation associated with nicotine dependence alters alpha2*-nicotinic acetylcholine receptor function. Neuropharmacology 79:715–725. https://doi.org/10.1016/j.neuropharm.2014.01.021
Davies P, Maloney AJ (1976) Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet 2:1403. https://doi.org/10.1016/s0140-6736(76)91936-x
de Jonge WJ et al (2005) Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2–STAT3 signaling pathway. Nat Immunol 6:844–851. https://doi.org/10.1038/ni1229
Deneris ES et al (1988) Primary structure and expression of beta 2: a novel subunit of neuronal nicotinic acetylcholine receptors. Neuron 1:45–54
Deneris ES, Boulter J, Swanson LW, Patrick J, Heinemann S (1989) Beta 3: a new member of nicotinic acetylcholine receptor gene family is expressed in brain. J Biol Chem 264:6268–6272
Di Angelantonio S, Matteoni C, Fabbretti E, Nistri A (2003) Molecular biology and electrophysiology of neuronal nicotinic receptors of rat chromaffin cells. Eur J Neurosci 17:2313–2322
Di Cesare ML, Cinci L, Micheli L, Zanardelli M, Pacini A, McIntosh JM, Ghelardini C (2014) alpha-conotoxin RgIA protects against the development of nerve injury-induced chronic pain and prevents both neuronal and glial derangement. Pain 155:1986–1995. https://doi.org/10.1016/j.pain.2014.06.023
Dichter MA, Tischler AS, Greene LA (1977) Nerve growth factor-induced increase in electrical excitability and acetylcholine sensitivity of a rat pheochromocytoma cell line. Nature 268:501–504
Dineley KT, Pandya AA, Yakel JL (2015) Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol Sci 36:96–108. https://doi.org/10.1016/j.tips.2014.12.002
Drenan RM et al (2010) Cholinergic modulation of locomotion and striatal dopamine release is mediated by alpha6alpha4* nicotinic acetylcholine receptors. J Neurosci 30:9877–9889. https://doi.org/10.1523/JNEUROSCI.2056-10.2010
Drisdel RC, Green WN (2000) Neuronal alpha-bungarotoxin receptors are alpha7 subunit homomers. J Neurosci 20:133–139
Drisdel RC, Manzana E, Green WN (2004) The role of palmitoylation in functional expression of nicotinic alpha7 receptors. J Neurosci 24:10502–10510. https://doi.org/10.1523/JNEUROSCI.3315-04.2004
Duvoisin RM, Deneris ES, Patrick J, Heinemann S (1989) The functional diversity of the neuronal nicotinic acetylcholine receptors is increased by a novel subunit: beta 4. Neuron 3:487–496
Elgoyhen AB, Johnson DS, Boulter J, Vetter DE, Heinemann S (1994) Alpha 9: an acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells. Cell 79:705–715
Exley R et al (2011) Distinct contributions of nicotinic acetylcholine receptor subunit alpha4 and subunit alpha6 to the reinforcing effects of nicotine. Proc Natl Acad Sci USA 108:7577–7582. https://doi.org/10.1073/pnas.1103000108
Falk L, Nordberg A, Seiger A, Kjaeldgaard A, Hellstrom-Lindahl E (2003) Higher expression of alpha7 nicotinic acetylcholine receptors in human fetal compared to adult brain. Brain Res Dev Brain Res 142:151–160
Flores CM, Rogers SW, Pabreza LA, Wolfe BB, Kellar KJ (1992) A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is up-regulated by chronic nicotine treatment. Mol Pharmacol 41:31–37
Forsayeth JR, Kobrin E (1997) Formation of oligomers containing the beta3 and beta4 subunits of the rat nicotinic receptor. J Neurosci 17:1531–1538
Forster I, Bertrand D (1995) Inward rectification of neuronal nicotinic acetylcholine receptors investigated by using the homomeric alpha 7 receptor. Proc Biol Sci 260:139–148. https://doi.org/10.1098/rspb.1995.0071
Fucile S (2004) Ca2+ permeability of nicotinic acetylcholine receptors. Cell Calcium 35:1–8
Fujita K, Lazarovici P, Guroff G (1989) Regulation of the differentiation of PC12 pheochromocytoma cells. Environ Health Perspect 80:127–142
Furukawa K, Nabekura J, Akaike N (1994) Nicotinic and muscarinic acetylcholine responses in differentiated PC12 cells. Brain Res 638:302–310
Garcia-Rates S, Camarasa J, Escubedo E, Pubill D (2007) Methamphetamine and 3,4-methylenedioxymethamphetamine interact with central nicotinic receptors and induce their up-regulation. Toxicol Appl Pharmacol 223:195–205. https://doi.org/10.1016/j.taap.2007.05.015
Garcia-Rates S, Camarasa J, Sanchez-Garcia AI, Gandia L, Escubedo E, Pubill D (2010) The effects of 3,4-methylenedioxymethamphetamine (MDMA) on nicotinic receptors: intracellular calcium increase, calpain/caspase 3 activation, and functional upregulation. Toxicol Appl Pharmacol 244:344–353. https://doi.org/10.1016/j.taap.2010.01.014
Ghio L et al (2015) Duration of untreated depression influences clinical outcomes and disability. J Affect Disord 175:224–228. https://doi.org/10.1016/j.jad.2015.01.014
Gotti C, Clementi F (2004) Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 74:363–396. https://doi.org/10.1016/j.pneurobio.2004.09.006
Gotti C et al (2010) Nicotinic acetylcholine receptors in the mesolimbic pathway: primary role of ventral tegmental area alpha6beta2* receptors in mediating systemic nicotine effects on dopamine release, locomotion, and reinforcement. J Neurosci 30:5311–5325. https://doi.org/10.1523/JNEUROSCI.5095-09.2010
Govind AP, Walsh H, Green WN (2012) Nicotine-induced upregulation of native neuronal nicotinic receptors is caused by multiple mechanisms. J Neurosci 32:2227–2238. https://doi.org/10.1523/JNEUROSCI.5438-11.2012
Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci USA 73:2424–2428
Groot-Kormelink PJ, Boorman JP, Sivilotti LG (2001) Formation of functional alpha3beta4alpha5 human neuronal nicotinic receptors in Xenopus oocytes: a reporter mutation approach. Br J Pharmacol 134:789–796. https://doi.org/10.1038/sj.bjp.0704313
Gubbins EJ, Gopalakrishnan M, Li J (2010) Alpha7 nAChR-mediated activation of MAP kinase pathways in PC12 cells. Brain Res 1328:1–11. https://doi.org/10.1016/j.brainres.2010.02.083
Gueorguiev VD, Zeman RJ, Hiremagalur B, Menezes A, Sabban EL (1999) Differing temporal roles of Ca2+ and cAMP in nicotine-elicited elevation of tyrosine hydroxylase mRNA. Am J Physiol 276:C54–65. https://doi.org/10.1152/ajpcell.1999.276.1.C54
Haghighi AP, Cooper E (2000) A molecular link between inward rectification and calcium permeability of neuronal nicotinic acetylcholine alpha3beta4 and alpha4beta2 receptors. J Neurosci 20:529–541
Harvey SC, McIntosh JM, Cartier GE, Maddox FN, Luetje CW (1997) Determinants of specificity for alpha-conotoxin MII on alpha3beta2 neuronal nicotinic receptors. Mol Pharmacol 51:336–342
Henderson LP, Gdovin MJ, Liu C, Gardner PD, Maue RA (1994) Nerve growth factor increases nicotinic ACh receptor gene expression and current density in wild-type and protein kinase A-deficient PC12 cells. J Neurosci 14:1153–1163
Hernandez CM, Dineley KT (2012) alpha7 nicotinic acetylcholine receptors in Alzheimer's disease: neuroprotective, neurotrophic or both? Curr Drug Targets 13:613–622
Hone AJ, Servent D, McIntosh JM (2018) alpha9-containing nicotinic acetylcholine receptors and the modulation of pain. Br J Pharmacol 175:1915–1927. https://doi.org/10.1111/bph.13931
Hu M, Whiting Theobald NL, Gardner PD (1994) Nerve growth factor increases the transcriptional activity of the rat neuronal nicotinic acetylcholine receptor beta 4 subunit promoter in transfected PC12 cells. J Neurochem 62:392–395
Ifune CK, Steinbach JH (1992) Inward rectification of acetylcholine-elicited currents in rat phaeochromocytoma cells. J Physiol 457:143–165
Ishii K, Wong JK, Sumikawa K (2005) Comparison of alpha2 nicotinic acetylcholine receptor subunit mRNA expression in the central nervous system of rats and mice. J Comp Neurol 493:241–260. https://doi.org/10.1002/cne.20762
Jurgensen S, Ferreira ST (2010) Nicotinic receptors, amyloid-beta, and synaptic failure in Alzheimer's disease. J Mol Neurosci 40:221–229. https://doi.org/10.1007/s12031-009-9237-0
Kalamida D et al (2007) Muscle and neuronal nicotinic acetylcholine receptors. Structure, function and pathogenicity. FEBS J 274:3799–3845. https://doi.org/10.1111/j.1742-4658.2007.05935.x
Kalkman HO, Feuerbach D (2016) Modulatory effects of alpha7 nAChRs on the immune system and its relevance for CNS disorders. Cell Mol Life Sci 73:2511–2530. https://doi.org/10.1007/s00018-016-2175-4
Katz E, Verbitsky M, Rothlin CV, Vetter DE, Heinemann SF, Elgoyhen AB (2000) High calcium permeability and calcium block of the alpha9 nicotinic acetylcholine receptor. Hear Res 141:117–128
Kihara T et al (2001) alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block A beta-amyloid-induced neurotoxicity. J Biol Chem 276:13541–13546. https://doi.org/10.1074/jbc.M008035200
King JR, Kabbani N (2016) Alpha 7 nicotinic receptor coupling to heterotrimeric G proteins modulates RhoA activation, cytoskeletal motility, and structural growth. J Neurochem 138:532–545. https://doi.org/10.1111/jnc.13660
King JR, Kabbani N (2018) Alpha 7 nicotinic receptors attenuate neurite development through calcium activation of calpain at the growth cone. PLoS ONE 13:e0197247. https://doi.org/10.1371/journal.pone.0197247
King JR, Nordman JC, Bridges SP, Lin MK, Kabbani N (2015) Identification and characterization of a G protein-binding cluster in alpha7 nicotinic acetylcholine receptors. J Biol Chem 290:20060–20070. https://doi.org/10.1074/jbc.M115.647040
King JR, Ullah A, Bak E, Jafri MS, Kabbani N (2018) Ionotropic and metabotropic mechanisms of allosteric modulation of alpha7 nicotinic receptor intracellular calcium. Mol Pharmacol 93:601–611. https://doi.org/10.1124/mol.117.111401
El Kouhen R, Hu M, Anderson DJ, Li J, Gopalakrishnan M (2009) Pharmacology of alpha7 nicotinic acetylcholine receptor mediated extracellular signal-regulated kinase signalling in PC12 cells. Br J Pharmacol 156:638–648. https://doi.org/10.1111/j.1476-5381.2008.00069.x
Koval L et al (2011) Differential involvement of alpha4beta2, alpha7 and alpha9alpha10 nicotinic acetylcholine receptors in B lymphocyte activation in vitro. Int J Biochem Cell Biol 43:516–524. https://doi.org/10.1016/j.biocel.2010.12.003
Kuryatov A, Onksen J, Lindstrom J (2008) Roles of accessory subunits in alpha4beta2(*) nicotinic receptors. Mol Pharmacol 74:132–143. https://doi.org/10.1124/mol.108.046789
Lee CH et al (2010) Overexpression and activation of the alpha9-nicotinic receptor during tumorigenesis in human breast epithelial cells. J Natl Cancer Inst 102:1322–1335. https://doi.org/10.1093/jnci/djq300
Levin ED, Bradley A, Addy N, Sigurani N (2002) Hippocampal alpha 7 and alpha 4 beta 2 nicotinic receptors and working memory. Neuroscience 109:757–765
Li Y, King MA, Grimes J, Smith N, de Fiebre CM, Meyer EM (1999a) Alpha7 nicotinic receptor mediated protection against ethanol-induced cytotoxicity in PC12 cells. Brain Res 816:225–228
Li Y, Papke RL, He YJ, Millard WJ, Meyer EM (1999b) Characterization of the neuroprotective and toxic effects of alpha7 nicotinic receptor activation in PC12 cells. Brain Res 830:218–225
Li Y, Meyer EM, Walker DW, Millard WJ, He YJ, King MA (2002) Alpha7 nicotinic receptor activation inhibits ethanol-induced mitochondrial dysfunction, cytochrome c release and neurotoxicity in primary rat hippocampal neuronal cultures. J Neurochem 81:853–858
Lips KS, Pfeil U, Kummer W (2002) Coexpression of alpha 9 and alpha 10 nicotinic acetylcholine receptors in rat dorsal root ganglion neurons. Neuroscience 115:1–5
Liu Q, Huang Y, Shen J, Steffensen S, Wu J (2012) Functional alpha7beta2 nicotinic acetylcholine receptors expressed in hippocampal interneurons exhibit high sensitivity to pathological level of amyloid beta peptides. BMC Neurosci 13:155. https://doi.org/10.1186/1471-2202-13-155
Lukas RJ (1991) Effects of chronic nicotinic ligand exposure on functional activity of nicotinic acetylcholine receptors expressed by cells of the PC12 rat pheochromocytoma or the TE671/RD human clonal line. J Neurochem 56:1134–1145
Luo S, Kulak JM, Cartier GE, Jacobsen RB, Yoshikami D, Olivera BM, McIntosh JM (1998) alpha-conotoxin AuIB selectively blocks alpha3 beta4 nicotinic acetylcholine receptors and nicotine-evoked norepinephrine release. J Neurosci 18:8571–8579
Mansvelder HD, Keath JR, McGehee DS (2002) Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33:905–919. https://doi.org/10.1016/s0896-6273(02)00625-6
Marrero MB, Bencherif M (2009) Convergence of alpha 7 nicotinic acetylcholine receptor-activated pathways for anti-apoptosis and anti-inflammation: central role for JAK2 activation of STAT3 and NF-kappaB. Brain Res 1256:1–7. https://doi.org/10.1016/j.brainres.2008.11.053
Martin EJ, Panickar KS, King MA, Deyrup M, Hunter BE, Wang GH, Meyer EM (1994) Cytoprotective actions of 2,4-dimethoxybenzylidene anabaseine in differentiated Pc12 cells and septal cholinergic neurons. Drug Dev Res 31:135–141. https://doi.org/10.1002/ddr.430310208
Mathie A, Cull-Candy SG, Colquhoun D (1987) Single-channel and whole-cell currents evoked by acetylcholine in dissociated sympathetic neurons of the rat. Proc R Soc Lond B Biol Sci 232:239–248. https://doi.org/10.1098/rspb.1987.0072
Mathie A, Colquhoun D, Cull-Candy SG (1990) Rectification of currents activated by nicotinic acetylcholine receptors in rat sympathetic ganglion neurones. J Physiol 427:625–655. https://doi.org/10.1113/jphysiol.1990.sp018191
Mathie A, Cull-Candy SG, Colquhoun D (1991) Conductance and kinetic properties of single nicotinic acetylcholine receptor channels in rat sympathetic neurones. J Physiol 439:717–750. https://doi.org/10.1113/jphysiol.1991.sp018690
Mohammadi SA, Burton TJ, Christie MJ (2017) alpha 9-nAChR knockout mice exhibit dysregulation of stress responses, affect and reward-related behaviour. Behav Brain Res 328:105–114. https://doi.org/10.1016/j.bbr.2017.04.005
Moretti M et al (2014) The novel alpha7beta2-nicotinic acetylcholine receptor subtype is expressed in mouse and human basal forebrain: biochemical and pharmacological characterization. Mol Pharmacol 86:306–317. https://doi.org/10.1124/mol.114.093377
Moroni M, Zwart R, Sher E, Cassels BK, Bermudez I (2006) alpha4beta2 nicotinic receptors with high and low acetylcholine sensitivity: pharmacology, stoichiometry, and sensitivity to long-term exposure to nicotine. Mol Pharmacol 70:755–768. https://doi.org/10.1124/mol.106.023044
Mucchietto V et al (2018) alpha9- and alpha7-containing receptors mediate the pro-proliferative effects of nicotine in the A549 adenocarcinoma cell line. Br J Pharmacol 175:1957–1972. https://doi.org/10.1111/bph.13954
Murray TA et al (2012) alpha7beta2 nicotinic acetylcholine receptors assemble, function, and are activated primarily via their alpha7-alpha7 interfaces. Mol Pharmacol 81:175–188. https://doi.org/10.1124/mol.111.074088
Nakayama H, Ueno S, Ikeuchi T, Hatanaka H (2000) Regulation of alpha3 nicotinic acetylcholine receptor subunit mRNA levels by nerve growth factor and cyclic AMP in PC12 cells. J Neurochem 74:1346–1354
Nashmi R, Lester HA (2006) CNS localization of neuronal nicotinic receptors. J Mol Neurosci 30:181–184. https://doi.org/10.1385/JMN:30:1:181
Nelson ME, Kuryatov A, Choi CH, Zhou Y, Lindstrom J (2003) Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors. Mol Pharmacol 63:332–341
Nery AA, Resende RR, Martins AH, Trujillo CA, Eterovic VA, Ulrich H (2010) Alpha 7 nicotinic acetylcholine receptor expression and activity during neuronal differentiation of PC12 pheochromocytoma cells. J Mol Neurosci 41:329–339. https://doi.org/10.1007/s12031-010-9369-2
Nery AA et al (2013) Rescue of amyloid-Beta-induced inhibition of nicotinic acetylcholine receptors by a peptide homologous to the nicotine binding domain of the alpha 7 subtype. PLoS ONE 8:e67194. https://doi.org/10.1371/journal.pone.0067194
Newhouse PA, Potter A, Singh A (2004) Effects of nicotinic stimulation on cognitive performance. Curr Opin Pharmacol 4:36–46. https://doi.org/10.1016/j.coph.2003.11.001
Nicholatos JW et al (2018) Nicotine promotes neuron survival and partially protects from Parkinson's disease by suppressing SIRT6. Acta Neuropathol Commun 6:120. https://doi.org/10.1186/s40478-018-0625-y
Nordman JC, Kabbani N (2012) An interaction between alpha7 nicotinic receptors and a G-protein pathway complex regulates neurite growth in neural cells. J Cell Sci 125:5502–5513. https://doi.org/10.1242/jcs.110379
Nordman JC, Kabbani N (2014) Microtubule dynamics at the growth cone are mediated by alpha7 nicotinic receptor activation of a Galphaq and IP3 receptor pathway. FASEB J 28:2995–3006. https://doi.org/10.1096/fj.14-251439
Le Novere N, Zoli M, Changeux JP (1996) Neuronal nicotinic receptor alpha 6 subunit mRNA is selectively concentrated in catecholaminergic nuclei of the rat brai. Eur J Neurosci 8:2428–2439
Le Novere N, Corringer PJ, Changeux JP (2002) The diversity of subunit composition in nAChRs: evolutionary origins, physiologic and pharmacologic consequences. J Neurobiol 53:447–456. https://doi.org/10.1002/neu.10153
Oliveira MT, Rego AC, Morgadinho MT, Macedo TR, Oliveira CR (2002) Toxic effects of opioid and stimulant drugs on undifferentiated PC12 cells. Ann N Y Acad Sci 965:487–496
O'Neill MJ, Murray TK, Lakics V, Visanji NP, Duty S (2002) The role of neuronal nicotinic acetylcholine receptors in acute and chronic neurodegeneration. Curr Drug Targets CNS Neurol Disord 1:399–411. https://doi.org/10.2174/1568007023339166
Pacini A, Micheli L, Maresca M, Branca JJ, McIntosh JM, Ghelardini C, Di Cesare ML (2016) The alpha9alpha10 nicotinic receptor antagonist alpha-conotoxin RgIA prevents neuropathic pain induced by oxaliplatin treatment. Exp Neurol 282:37–48. https://doi.org/10.1016/j.expneurol.2016.04.022
Pandya A, Yakel JL (2011) Allosteric modulators of the alpha4beta2 subtype of neuronal nicotinic acetylcholine receptors. Biochem Pharmacol 82:952–958. https://doi.org/10.1016/j.bcp.2011.04.020
Parri HR, Hernandez CM, Dineley KT (2011) Research update: Alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer's disease. Biochem Pharmacol 82:931–942. https://doi.org/10.1016/j.bcp.2011.06.039
Patrick J, Stallcup B (1977) alpha-Bungarotoxin binding and cholinergic receptor function on a rat sympathetic nerve line. J Biol Chem 252:8629–8633
Pena G, Cai B, Liu J, van der Zanden EP, Deitch EA, de Jonge WJ, Ulloa L (2010) Unphosphorylated STAT3 modulates alpha 7 nicotinic receptor signaling and cytokine production in sepsis. Eur J Immunol 40:2580–2589. https://doi.org/10.1002/eji.201040540
Peng H, Ferris RL, Matthews T, Hiel H, Lopez-Albaitero A, Lustig LR (2004) Characterization of the human nicotinic acetylcholine receptor subunit alpha (alpha) 9 (CHRNA9) and alpha (alpha) 10 (CHRNA10) in lymphocytes. Life Sci 76:263–280. https://doi.org/10.1016/j.lfs.2004.05.031
Perez XA, Bordia T, McIntosh JM, Quik M (2010) alpha6ss2* and alpha4ss2* nicotinic receptors both regulate dopamine signaling with increased nigrostriatal damage: relevance to Parkinson's disease. Mol Pharmacol 78:971–980. https://doi.org/10.1124/mol.110.067561
Pettit DL, Shao Z, Yakel JL (2001) beta-Amyloid(1–42) peptide directly modulates nicotinic receptors in the rat hippocampal slice. J Neurosci 21:RC120
Philip NS, Carpenter LL, Tyrka AR, Price LH (2010) Nicotinic acetylcholine receptors and depression: a review of the preclinical and clinical literature. Psychopharmacology 212:1–12. https://doi.org/10.1007/s00213-010-1932-6
Picciotto MR et al (1998) Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391:173–177. https://doi.org/10.1038/34413
Pons S et al (2008) Crucial role of alpha4 and alpha6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration. J Neurosci 28:12318–12327. https://doi.org/10.1523/JNEUROSCI.3918-08.2008
Quik M, Bordia T, O'Leary K (2007) Nicotinic receptors as CNS targets for Parkinson's disease. Biochem Pharmacol 74:1224–1234. https://doi.org/10.1016/j.bcp.2007.06.015
Quik M, Bordia T, Huang L, Perez X (2011) Targeting nicotinic receptors for Parkinson's disease therapy. CNS Neurol Disord Drug Targets 10:651–658
Quik M, Park KM, Hrachova M, Mallela A, Huang LZ, McIntosh JM, Grady SR (2012) Role for alpha6 nicotinic receptors in l-dopa-induced dyskinesias in parkinsonian mice. Neuropharmacology 63:450–459. https://doi.org/10.1016/j.neuropharm.2012.04.029
Rahman S, Lopez-Hernandez GY, Corrigall WA, Papke RL (2008) Neuronal nicotinic receptors as brain targets for pharmacotherapy of drug addiction. CNS Neurol Disord Drug Targets 7:422–441
Ramirez-Latorre J, Yu CR, Qu X, Perin F, Karlin A, Role L (1996) Functional contributions of alpha5 subunit to neuronal acetylcholine receptor channels. Nature 380:347–351. https://doi.org/10.1038/380347a0
Rangwala F et al (1997) Neuronal alpha-bungarotoxin receptors differ structurally from other nicotinic acetylcholine receptors. J Neurosci 17:8201–8212
Ren K, Puig V, Papke RL, Itoh Y, Hughes JA, Meyer EM (2005) Multiple calcium channels and kinases mediate alpha7 nicotinic receptor neuroprotection in PC12 cells. J Neurochem 94:926–933. https://doi.org/10.1111/j.1471-4159.2005.03223.x
Rogers SW, Mandelzys A, Deneris ES, Cooper E, Heinemann S (1992) The expression of nicotinic acetylcholine receptors by PC12 cells treated with NGF. J Neurosci 12:4611–4623
Rosas-Ballina M, Tracey KJ (2009) Cholinergic control of inflammation. J Intern Med 265:663–679. https://doi.org/10.1111/j.1365-2796.2009.02098.x
Sabban EL, Gueorguiev VD (2002) Effects of short- and long-term nicotine treatment on intracellular calcium and tyrosine hydroxylase gene expression. Ann N Y Acad Sci 971:39–44. https://doi.org/10.1111/j.1749-6632.2002.tb04430.x
Sabec MH, Wonnacott S, Warburton EC, Bashir ZI (2018) Nicotinic acetylcholine receptors control encoding and retrieval of associative recognition memory through plasticity in the medial prefrontal cortex. Cell Rep 22:3409–3415. https://doi.org/10.1016/j.celrep.2018.03.016
Sala F, Nistri A, Criado M (2008) Nicotinic acetylcholine receptors of adrenal chromaffin cells. Acta Physiol (Oxf) 192:203–212. https://doi.org/10.1111/j.1748-1716.2007.01804.x
Sands SB, Barish ME (1991) Calcium permeability of neuronal nicotinic acetylcholine receptor channels in PC12 cells. Brain Res 560:38–42. https://doi.org/10.1016/0006-8993(91)91211-i
Sands SB, Barish ME (1992) Neuronal nicotinic acetylcholine receptor currents in phaeochromocytoma (PC12) cells: dual mechanisms of rectification. J Physiol 447:467–487
Seguela P, Wadiche J, Dineley-Miller K, Dani JA, Patrick JW (1993) Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium. J Neurosci 13:596–604
Shaw S, Bencherif M, Marrero MB (2002) Janus kinase 2, an early target of alpha 7 nicotinic acetylcholine receptor-mediated neuroprotection against Abeta-(1–42) amyloid. J Biol Chem 277:44920–44924. https://doi.org/10.1074/jbc.M204610200
Shimohama S, Kawamata J (2018) Roles of Nicotinic acetylcholine receptors in the pathology and treatment of Alzheimer's and Parkinson's diseases. In: Akaike A, Shimohama S, Misu Y (eds) Nicotinic acetylcholine receptor signaling in neuroprotection. Springer Press, Singapore city, pp 137–158. https://doi.org/10.1007/978-981-10-8488-1_8
Shimohama S et al (1998) Nicotinic alpha 7 receptors protect against glutamate neurotoxicity and neuronal ischemic damage. Brain Res 779:359–363
Sine SM (2012) End-plate acetylcholine receptor: structure, mechanism, pharmacology, and disease. Physiol Rev 92:1189–1234. https://doi.org/10.1152/physrev.00015.2011
Slotkin TA, MacKillop EA, Ryde IT, Tate CA, Seidler FJ (2007) Screening for developmental neurotoxicity using PC12 cells: comparisons of organophosphates with a carbamate, an organochlorine, and divalent nickel. Environ Health Perspect 115:93–101
Soll LG, Grady SR, Salminen O, Marks MJ, Tapper AR (2013) A role for alpha4(non-alpha6)* nicotinic acetylcholine receptors in motor behavior. Neuropharmacology 73:19–30. https://doi.org/10.1016/j.neuropharm.2013.05.001
Takada-Takatori Y, Kume T, Sugimoto M, Katsuki H, Sugimoto H, Akaike A (2006) Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology 51:474–486. https://doi.org/10.1016/j.neuropharm.2006.04.007
Takahashi T, Yamashita H, Nakamura S, Ishiguro H, Nagatsu T, Kawakami H (1999) Effects of nerve growth factor and nicotine on the expression of nicotinic acetylcholine receptor subunits in PC12 cells. Neurosci Res 35:175–181
Thomsen MS et al (2016) Lynx1 and Abeta1-42 bind competitively to multiple nicotinic acetylcholine receptor subtypes. Neurobiol Aging 46:13–21. https://doi.org/10.1016/j.neurobiolaging.2016.06.009
Tohgi H, Utsugisawa K, Nagane Y (2000) Protective effect of nicotine through nicotinic acetylcholine receptor alpha 7 on hypoxia-induced membrane disintegration and DNA fragmentation of cultured PC12 cells. Neurosci Lett 285:91–94
Tracey KJ (2007) Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 117:289–296. https://doi.org/10.1172/JCI30555
Trivisano M et al (2015) Mutation of CHRNA2 in a family with benign familial infantile seizures: Potential role of nicotinic acetylcholine receptor in various phenotypes of epilepsy. Epilepsia 56:e53–57. https://doi.org/10.1111/epi.12967
Utsugisawa K, Nagane Y, Obara D, Tohgi H (2002) Overexpression of alpha7 nicotinic acetylcholine receptor prevents G1-arrest and DNA fragmentation in PC12 cells after hypoxia. J Neurochem 81:497–505
Vailati S, Moretti M, Balestra B, McIntosh M, Clementi F, Gotti C (2000) beta3 subunit is present in different nicotinic receptor subtypes in chick retina. Eur J Pharmacol 393:23–30
Vallejo YF, Buisson B, Bertrand D, Green WN (2005) Chronic nicotine exposure upregulates nicotinic receptors by a novel mechanism. J Neurosci 25:5563–5572. https://doi.org/10.1523/JNEUROSCI.5240-04.2005
Valor LM, Campos-Caro A, Carrasco-Serrano C, Ortiz JA, Ballesta JJ, Criado M (2002) Transcription factors NF-Y and Sp1 are important determinants of the promoter activity of the bovine and human neuronal nicotinic receptor beta 4 subunit genes. J Biol Chem 277:8866–8876. https://doi.org/10.1074/jbc.M110454200
Vaudry D, Stork PJ, Lazarovici P, Eiden LE (2002) Signaling pathways for PC12 cell differentiation: making the right connections. Science 296:1648–1649. https://doi.org/10.1126/science.1071552
Verbitsky M, Rothlin CV, Katz E, Elgoyhen AB (2000) Mixed nicotinic-muscarinic properties of the alpha9 nicotinic cholinergic receptor. Neuropharmacology 39:2515–2524
Vetter DE et al (1999) Role of alpha9 nicotinic ACh receptor subunits in the development and function of cochlear efferent innervation. Neuron 23:93–103
Wang HY, Lee DH, D'Andrea MR, Peterson PA, Shank RP, Reitz AB (2000a) beta-Amyloid(1–42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology. J Biol Chem 275:5626–5632. https://doi.org/10.1074/jbc.275.8.5626
Wang HY, Lee DH, Davis CB, Shank RP (2000b) Amyloid peptide Abeta(1–42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors. J Neurochem 75:1155–1161. https://doi.org/10.1046/j.1471-4159.2000.0751155.x
Wang H et al (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421:384–388. https://doi.org/10.1038/nature01339
Weisstaub N, Vetter DE, Elgoyhen AB, Katz E (2002) The alpha9alpha10 nicotinic acetylcholine receptor is permeable to and is modulated by divalent cations. Hear Res 167:122–135
Wessler I, Kilbinger H, Bittinger F, Unger R, Kirkpatrick CJ (2003) The non-neuronal cholinergic system in humans: expression, function and pathophysiology. Life Sci 72:2055–2061
Westerink RH, Ewing AG (2008) The PC12 cell as model for neurosecretion. Acta Physiol (Oxf) 192:273–285. https://doi.org/10.1111/j.1748-1716.2007.01805.x
Whiteaker P et al (2007) Discovery, synthesis, and structure activity of a highly selective alpha7 nicotinic acetylcholine receptor antagonist. Biochemistry 46:6628–6638. https://doi.org/10.1021/bi7004202
Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 10:122–126. https://doi.org/10.1002/ana.410100203
Whiting P, Lindstrom J (1986) Pharmacological properties of immuno-isolated neuronal nicotinic receptors. J Neurosci 6:3061–3069
Whiting PJ, Schoepfer R, Swanson LW, Simmons DM, Lindstrom JM (1987) Functional acetylcholine receptor in PC12 cells reacts with a monoclonal antibody to brain nicotinic receptors. Nature 327:515–518. https://doi.org/10.1038/327515a0
Whiting PJ et al (1991) Expression of nicotinic acetylcholine receptor subtypes in brain and retina. Brain Res Mol Brain Res 10:61–70
Yakel JL (2014) Nicotinic ACh receptors in the hippocampal circuit; functional expression and role in synaptic plasticity. J Physiol 592:4147–4153. https://doi.org/10.1113/jphysiol.2014.273896
Yang X, Fyodorov D, Deneris ES (1995) Transcriptional analysis of acetylcholine receptor alpha 3 gene promoter motifs that bind Sp1 and AP2. J Biol Chem 270:8514–8520
Yoshikawa H et al (2006) Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-kappaB phosphorylation and nuclear factor-kappaB transcriptional activity through nicotinic acetylcholine receptor alpha7. Clin Exp Immunol 146:116–123. https://doi.org/10.1111/j.1365-2249.2006.03169.x
Zhang JC et al (2016) Depression-like phenotype by deletion of alpha7 nicotinic acetylcholine receptor: Role of BDNF-TrkB in nucleus accumbens. Sci Rep 6:36705. https://doi.org/10.1038/srep36705
Zoli M, Moretti M, Zanardi A, McIntosh JM, Clementi F, Gotti C (2002) Identification of the nicotinic receptor subtypes expressed on dopaminergic terminals in the rat striatum. J Neurosci 22:8785–8789
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Mussina, K., Toktarkhanova, D. & Filchakova, O. Nicotinic Acetylcholine Receptors of PC12 Cells. Cell Mol Neurobiol 41, 17–29 (2021). https://doi.org/10.1007/s10571-020-00846-x
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DOI: https://doi.org/10.1007/s10571-020-00846-x