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The Journal of Neuroscience, April 15, 1999, 19(8):2945-2953

Calcitonin Gene-Related Peptide Rapidly Downregulates Nicotinic Receptor Function and Slowly Raises Intracellular Ca²⁺ in Rat Chromaffin Cells In Vitro

R. Giniatullin^{1, 3}, Silvia Di Angelantonio^{1, 2}, Cristina Marchetti¹, Elena Sokolova^{1, 3}, L. Khiroug^{1, 2}, and A. Nistri^{1, 2}

¹ Biophysics Sector and ² Istituto Nazionale di Fisica della Materia Unit, International School for Advanced Studies (SISSA), 34014 Trieste, Italy, and ³ Physiology Department, Kazan Medical University, 42000 Kazan, Russia

Although calcitonin gene-related peptide (CGRP) modulates muscle-type nicotinic acetylcholine receptors (nAChRs) via intracellular second messenger-mediated phosphorylation, the action of this peptide on neuronal-type nAChRs remains unknown. Using neuronal nAChRs of rat chromaffin cells in vitro we studied the effect of CGRP, which is physiologically present in adrenal medulla, on membrane currents and [Ca²⁺]_i transients elicited by nicotine. Our main novel observation was that CGRP (either bath-applied or focally applied for a few seconds or even co-applied with nicotine for a few milliseconds) selectively and rapidly blocked nAChRs (a phenomenon unlikely caused by intracellular messengers in view of its speed) without affecting GABA receptors. The inhibitory effect of CGRP was independent of [Ca²⁺]_i or membrane potential and not accompanied by baseline current changes. Like the competitive antagonist N,N,N-trimethyl-1-(4-trans-stilbenoxy)-2-propilammonium, CGRP induced a rightward, parallel shift of the nicotine dose-response curve; during co-application of these blockers the nicotine dose-ratio value was the sum of the values obtained with each antagonist alone. The block by CGRP was insensitive to the receptor antagonist hCGRP_8-37 but mimicked by CGRP_1-7. Persistent application of CGRP slowly increased [Ca²⁺]_i, a phenomenon independent from external Ca²⁺, thus implying Ca²⁺ release from internal stores, and suppressed by hCGRP_8-37. CGRP_1-7 had no significant effect on [Ca²⁺]_i. We propose that the 1-7 amino acid sequence of CGRP was responsible for the direct, rapid block of nAChRs, whereas the full-length peptide molecule was necessary for the delayed rise in internal Ca²⁺ potentially able to trigger phosphorylation-dependent modulation of nicotinic receptor function.

Key words: CGRP; CGRP antagonist; neuropeptide; nicotine; calcium imaging; intracellular calcium; receptor modulation

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Copyright © 1999 Society for Neuroscience  0270-6474/99/1982945-09$05.00/0

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