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Human nicotinic receptors in chromaffin cells: characterization and pharmacology

  • Almudena AlbillosEmail author
  • J. Michael McIntosh
Invited Review

Abstract

During the last 10 years, we have been working on human chromaffin cells obtained from the adrenal gland of organ donors that suffered encephalic or cardiac death. We first electrophysiologically characterized the nicotinic acetylcholine receptors (nAChRs) activated by acetylcholine, and their contribution to the exocytosis of chromaffin vesicles and release of catecholamines. We have shown that these cells possess an adrenergic phenotype. This phenotype may contribute to an increased expression of α7 nAChRs in these cells, allowing for recording of α7 nAChR currents, something that had previously not been achieved in non-human species. The use of α-conotoxins allowed us to characterize non-α7 nAChR subtypes and, together with molecular biology experiments, conclude that the predominant nAChR subtype in human chromaffin cells is α3β4* (asterisk indicates the posible presence of additional subunits). In addition, there is a minor population of αxβ2 nAChRs. Both α7 and non-α7 nAChR subtypes contribute to the exocytotic process. Exocytosis mediated by nAChRs could be as large in magnitude as that elicited by calcium entry through voltage-dependent calcium channels. Finally, we have also investigated the effect of nAChR-targeted tobacco cessation drugs on catecholamine release in chromaffin cells. We have concluded that at therapeutic concentrations, varenicline alone does not increase the frequency of action potentials evoked by ACh. However, varenicline in the presence of nicotine does increase this frequency, and thus, in the presence of both drugs, the probability of increased catecholamine release in human chromaffin cells is high.

Keywords

Human Chromaffin cells Nicotinic receptors α-conotoxins Varenicline Nicotine Patch-clamp 

Notes

Acknowledgements

This review is devoted to Prof. Antonio García, for his fervor and dedication to scientific research. And all anonymous organ donors and their families, for their generosity and collaboration in our scientific work.

Funding information

This work was supported by grants from the Spanish Government (BFU2005-00743, BFU2008-01382/BFI, BFU2011-27690 to A.A.), the Spanish Ministerio de Economía, Industria y Competitividad (BFU2012-30997 and BFU2015-69092 to A.A.), the European Research Agency (NRHACC-329956 to A.A.), and the US National Institutes of Health (GM48677 and GM103801 to J.M.M).

References

  1. 1.
    Alkondon M, Pereira EF, Albuquerque EX (1998) Alpha-Bungarotoxin- and methyllycaconitine-sensitive nicotinic receptors mediate fast synaptic transmission in interneurons of rat hippocampal slices. Brain Res 810:257–263CrossRefPubMedGoogle Scholar
  2. 2.
    Almazan G, Aunis D, García AG, Montiel C, Nicolás GP, Sáncez-Gacía P (1984) Effects of collagenase on the release of [3H]-noradrenaline from bovine cultured adrenal chromaffin cells. Br J Pharmacol 81:599–561CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Azam L, McIntosh JM (2012) Molecular basis for the differential sensitivity of rat and human α9α10 nAChRs to α-conotoxin RgIA. J Neurochem 122:1137–1144CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Azam L, Maskos U, Changeux JP, Dowell CD, Christensen S, De Biasi M, McIntosh JM (2010) α-Conotoxin BuIA[T5A;P6O]: a novel ligand that discriminates between α6ß4 and α6ß2 nicotinic acetylcholine receptors and blocks nicotine-stimulated norepinephrine release. FASEB J 24:5113–5123Google Scholar
  5. 5.
    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 17:6094–6104PubMedGoogle Scholar
  6. 6.
    Campling BG, Kuryatov A, Lindstrom J (2013) Acute activation, desensitization and smoldering activation of human acetylcholine receptors. PLoS One 8:e79653CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Campos-Caro A, Smillie FI, Dominguez del Toro E, Rovira JC, Vicente-Agullo F, Chapuli J, Juiz JM, Sala S, Sala F, Ballesta JJ, Criado M (1997) Neuronal nicotinic acetylcholine receptors on bovine chromaffin cells: cloning, expression, and genomic organization of receptor subunits. J Neurochem 68:488–497CrossRefPubMedGoogle Scholar
  8. 8.
    Capelli AM, Castelletti L, Chen YH et al (2011) Stable expression and functional characterization of a human nicotinic acetylcholine receptor with alpha6beta2 properties: discovery of selective antagonists. Br J Pharmacol 163:313–329CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Carrasco-Serrano C, Criado M (2004) Glucocorticoid activation of the neuronal nicotinic acetylcholine receptor α7 subunit gene: involvemente of transcripticon factor Egr-1. FEBS Lett 566:247–250CrossRefPubMedGoogle Scholar
  10. 10.
    Chang PH, Chiang CH, Ho WC, Wu PZ, Tsai JS, Guo FR (2015) Combination therapy of varenicline with nicotine replacement therapy is better than varenicline alone: a systematic review and meta-analysis of randomized controlled trials. BMC Public Health 15:689CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    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 30:6732–6742CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Criado M, Domínguez del Toro E, Carrasco-Serrano C, Smillie FI, Juíz JM, Viniegra S, Ballesta JJ (1997) Differential expression of alpha-bungarotoxin-sensitive neuronal nicotinic receptors in adrenergic chromaffin cells: a role for transcription factor Egr-1. J Neurosci 17:6554–6564PubMedGoogle Scholar
  13. 13.
    Del Barrio L, Egea J, Leon R, Romero A, Ruiz A, Montero M, Alvarez J, López MG (2011) Calcium signalling mediated through alpha7 and non-alpha7 nAChR stimulation is differentially regulated in bovine chromaffin cells to induce catecholamine release. Br J Pharmacol 162:94–110CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    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 17:2313–2322CrossRefPubMedGoogle Scholar
  15. 15.
    Drisdel RC, Green WN (2000) Neuronal alpha-bungarotoxin receptors are alpha7 subunit homomers. J Neurosci 20:133–139PubMedGoogle Scholar
  16. 16.
    El-Hajj RA, McKay SB, McKay DB (2007) Pharmacological and immunological identification of native alpha7 nicotinic receptors: evidence for homomeric and heteromeric alpha7 receptors. Life Sci 81:1317–1322CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Frazier CJ, Buhler AV, Weiner JL, Dunwiddie TV (1998) Synaptic potentials mediated via alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in rat hippocampal interneurons. J Neurosci 18:8228–8235PubMedGoogle Scholar
  18. 18.
    García-Guzmán M, Sala F, Sala S, Campos-Caro A, Stuhmer W, Gutierrez LM, Criado M (1995) alpha-Bungarotoxin-sensitive nicotinic receptors on bovine chromaffin cells: molecular cloning, functional expression and alternative splicing of the alpha 7 subunit. Eur J Neurosci 7:647–655CrossRefPubMedGoogle Scholar
  19. 19.
    Hernandez-Vivanco A, Hone AJ, Scadden M, Carmona Hidalgo B, McIntosh JM, Albillos A (2014) Monkey adrenal chromaffin cells express α6β4* nicotinic acetylcholine receptors. PLoS One 9(4):e94142CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hone AJ, Ruiz M, Scadden M, Christensen S, Gajewiak J, Azam L, McIntosh JM (2013) Positional scanning mutagenesis of α-conotoxin PeIA identifies critical residues that confer potency and selectivity for α6/α3β2β3 and α3β2 nicotinic acetylcholine receptors. J Biol Chem 288:25428–25439Google Scholar
  21. 21.
    Hone AJ, McIntosh JM, Azam L, Lindstrom J, Lucero L, Whiteaker P, Passas J, Blazquez J, Albillos A (2015) α-Conotoxins identify the α3β4 subtype as the predominant nicotinic acetylcholine receptor expressed in human adrenal chromaffin cells. Mol Pharmacol 88:881–893CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Hone AJ, McIntosh JM, Rueda-Ruzafa L, Passas J, De Castro-Guerín C, Blazquez J, González-Enguita C, Lindstrom J, Albillos A (2017) Therapeutic concentrations of varenicline and nicotine increase action potential firing in human adrenal chromaffin cells. J Neuroch 140:37–52CrossRefGoogle Scholar
  23. 23.
    Hukkanen J, Ukkola O, Benowitz NL (2010) Varenicline and pheochromocytoma. Ann Intern Med 152:335–336CrossRefPubMedGoogle Scholar
  24. 24.
    Innocent N, Livingstone PD, Hone A, Kimura A, Young T, Whiteaker P, McIntosh JM, Wonnacott S (2008) Alpha-conotoxin Arenatus IB[V11L,V16D] [corrected] is a potent and selective antagonist at rat and human native alpha7 nicotinic acetylcholine receptors. J Pharmacol Exp Ther 327:529–537CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kilpatrick DL, Slepetis R, Kirshner N (1981) Inhibition of catecholamine secretion from adrenal medulla cells by neurotoxins and cholinergic antagonists. J Neurochem 37:125–131CrossRefPubMedGoogle Scholar
  26. 26.
    Kumakura K, Karoum F, Guidotti A, Costa E (1980) Modulation of nicotinic receptors by opiate receptor agonists in cultured adrenal chromaffin cells. Nature 283:489–492CrossRefPubMedGoogle Scholar
  27. 27.
    López MG, Montiel C, Herrero CJ, García-Palomero E, Mayorgas I, Hernandez-Guijo JM, Villarroya M, Olivares R, Gandia L, McIntosh JM, Olivera BM, García AG (1998) Unmasking the functions of the chromaffin cell alpha7 nicotinic receptor by using short pulses of acetylcholine and selective blockers. Proc Natl Acad Sci U S A 95:14184–14189CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    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 18:8571–8579Google Scholar
  29. 29.
    Luo S, Zhangsun D, Wu Y, Zhu X, Hu Y, McIntyre M, Christensen S, Akcan M, Craik DJ, McIntosh JM (2013) Characterization of a novel a-conotoxin from conus textile that selectively targets a6/a3b2b3 nicotinic acetylcholine receptors. J Biol Chem 288:894–902Google Scholar
  30. 30.
    McIntosh JM, Azam L, Staheli S, Dowell C, Lindstrom JM, Kuryatov A, Garrett JE, Marks MJ, Whiteaker P (2004) Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors. Mol Pharmacol 65:944–952CrossRefPubMedGoogle Scholar
  31. 31.
    Mihalak KB, Carroll FI, Luetje CW (2006) Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors. Mol Pharmacol 70:801–805CrossRefPubMedGoogle Scholar
  32. 32.
    Mousavi M, Hellstrom-Lindahl E, Guan ZZ, Bednar I, Nordberg A (2001) Expression of nicotinic acetylcholine receptors in human and rat adrenal medulla. Life Sci 70:577–590CrossRefPubMedGoogle Scholar
  33. 33.
    Pérez-Alvarez A, Albillos A (2007) Key role of the nicotinic receptor in neurotransmitter exocytosis in human chromaffin cells. J Neurochem 103:2281–2290CrossRefPubMedGoogle Scholar
  34. 34.
    Pérez-Alvarez A, Hernandez-Vivanco A, Cano-Abad M, Albillos A (2008) Pharmacological and biophysical properties of Ca2+ channels and subtype distributions in human adrenal chromaffin cells. Pflugers Arch 456:1149–1162CrossRefPubMedGoogle Scholar
  35. 35.
    Pérez-Alvarez A, Hernandez-Vivanco A, Gregorio SA, Tabernero A, McIntosh JM, AlbillosA (2012a) Pharmacological characterization of native α7 nAChRs and their contribution to depolarization-elicited exocytosis in human chromaffin cells. Br J Pharmacol 165:908–921CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Pérez-Alvarez A, Hernandez-Vivanco A, McIntosh JM, Albillos A (2012b) Native α6β4* nicotinic receptors control exocytosis in human chromaffin cells of the adrenal gland. FASEB J 26:346–354CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Prochaska JJ, Hilton JF (2012) Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis. BMJ 344:e2856CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Quik M, Geertsen S, Trifaró JM (1987) Marked up-regulation of the beta-bungarotoxin site in adrenal chromaffin cells by specific nicotinic antagonists. Mol Pharmacol 31:385–391PubMedGoogle Scholar
  39. 39.
    Rollema H, Chambers LK, Coe JW et al (2007) Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology 52:985–994CrossRefPubMedGoogle Scholar
  40. 40.
    Rollema H, Russ C, Lee TC, Hurst RS, Bertrand D (2014) Functional interactions of varenicline and nicotine with nAChR subtypes implicated in cardiovascular control. Nicotine Tob Res 16:733–742CrossRefPubMedGoogle Scholar
  41. 41.
    Rust G, Burgunder JM, Lauterburg TE, Cachelin AB (1994) Expression of neuronal nicotinic acetylcholine receptor subunit genes in the rat autonomic nervous system. Eur J Neurosci 6:478–485CrossRefPubMedGoogle Scholar
  42. 42.
    Singh S, Loke YK, Spangler JG, Furberg CD (2011) Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis. CMAJ 183:1359–1366CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Stokes C, Papke RL (2012) Use of an alpha3beta4 nicotinic acetylcholine receptor subunit concatamer to characterize ganglionic receptor subtypes with specific subunit composition reveals species-specific pharmacologic properties. Neuropharmacology 63:538–546CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Smith NJ, Hone AJ, Memon T, Bossi S, Smith TE, McIntosh JM, Olivera BM, Teichert RW (2013) Comparative functional expression of nAChR subtypes in rodent DRG neurons. Front Cell Neurosci 7:225Google Scholar
  45. 45.
    Tachikawa E, Mizuma K, Kudo K, Kashimoto T, Yamato S, Ohta S (2001) Characterization of the functional subunit combination of nicotinic acetylcholine receptors in bovine adrenal chromaffin cells. Neurosci Lett 312:161–164CrossRefPubMedGoogle Scholar
  46. 46.
    Tammimaki A, Herder P, Li P, Esch C, Laughlin JR, Akk G, Stitzel JA (2012) Impact of human D398N single nucleotide polymorphism on intracellular calcium response mediated by alpha3beta4alpha5 nicotinic acetylcholine receptors. Neuropharmacology 63:1002–1011CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Trifaró JM, Lee RW (1980) Morphological characteristics and stimulus-secretion coupling in bovine adcrenal chromaffin cell cultures. Neuroscience 5:1533–1546CrossRefPubMedGoogle Scholar
  48. 48.
    Ullian EM, McIntosh JM, Sargent PB (1997) Rapid synaptic transmission in the avian ciliary ganglion is mediated by two distinct classes of nicotinic receptors. J Neurosci 17:7210–7219PubMedGoogle Scholar
  49. 49.
    Wilson SP, Kirshner N (1977) The acetylcholine receptor of the adrenal medulla. J Neurochem 28:687–695CrossRefPubMedGoogle Scholar
  50. 50.
    Wong DL (2003) Why is the adrenal adrenergic? Endocr Pathol 14:25–36CrossRefPubMedGoogle Scholar
  51. 51.
    Wurtman RJ, Axelrod J (1965) Adrenaline synthesis: control by the pituitary gland and adrenal glucocorticoids. Science 150:1464–1465CrossRefPubMedGoogle Scholar
  52. 52.
    Yu R, Kompella SN, Adams DJ, Craik DJ, Kaas Q (2013) Determination of the α-conotoxin Vc1.1 binding site on the α9α10 nicotinic acetylcholine receptor. J Med Chem 56:3557–3567CrossRefPubMedGoogle Scholar
  53. 53.
    Zhang ZW, Coggan JS, Berg DK (1996) Synaptic currents generated by neuronal acetylcholine receptors sensitive to alpha-bungarotoxin. Neuron 17:1231–1240CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Departamento de Farmacología y Terapéutica, Facultad de MedicinaUniversidad Autónoma de MadridMadridSpain
  2. 2.George E. Whalen Veterans Affairs Medical CenterSalt Lake CityUSA
  3. 3.Department of BiologyUniversity of UtahSalt Lake CityUSA
  4. 4.Department of PsychiatryUniversity of UtahSalt Lake CityUSA

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