PT  - JOURNAL ARTICLE
AU  - Di Angelantonio, Silvia
AU  - Costa, Valeria
AU  - Carloni, Paolo
AU  - Messori, Luigi
AU  - Nistri, Andrea
TI  - A Novel Class of Peptides with Facilitating Action on Neuronal Nicotinic Receptors of Rat Chromaffin Cells in Vitro: Functional and Molecular Dynamics Studies
AID  - 10.1124/mol.61.1.43
DP  - 2002 Jan 01
TA  - Molecular Pharmacology
PG  - 43--54
VI  - 61
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/61/1/43.short
4100  - http://molpharm.aspetjournals.org/content/61/1/43.full
SO  - Mol Pharmacol2002 Jan 01; 61
AB  - Peptides related to the N-terminal region of calcitonin gene-related peptide (CGRP) were tested for their ability to modulate neuronal nicotinic acetylcholine receptors (nAChRs) of rat cultured chromaffin cells under whole cell patch-clamp conditions. Although CGRP1–7 and CGRP2–7 depressed responses mediated by nAChRs, CGRP1–6, CGRP1–5, or CGRP1–4 rapidly and reversibly potentiated submaximal nicotine currents while sparing maximal currents. CGRP1–3was inactive. The threshold concentration for the enhancing effect of CGRP1–6 was 0.1 μM. CGRP1–5 or CGRP1–4 were less effective than CGRP1–6. Coapplication of CGRP1–6 and of the allosteric potentiator physostigmine (0.5 μM) gave additive effects on nicotine currents. CGRP1–6 did not enhance responses generated by muscle-type nicotinic receptors of cultured myoblasts or by γ-aminobutyric acidA receptors expressed by human embryonic kidney cells. Molecular dynamics (MD) simulations suggested that CGRP1–7exhibited a relatively rigid ring structure imparted by the disulfide bridge between Cys2 and Cys7. The circular dichroism (CD) spectrum recorded from the same peptide was in agreement with this result. Shorter peptides, missing such a bridge, exhibited propensity for α-helix configuration. Replacing Cys7 with Ala yielded CGRP1–7A, a fragment with partial α-helix structure and ability to enhance nicotine currents. CD measurements on CGRP1–6 were compatible with these MD structural findings. Short terminal fragments of CGRP represent a novel class of substances with selective, rapid, and reversible potentiation of nAChRs.