USE-DEPENDENT SUPPRESSION OF THE NICOTINIC ACETYLCHOLINE-RECEPTOR RESPONSE BY THE PROADRENOMEDULLIN N-TERMINAL 20-AMINO ACID PEPTIDE IN RATLOCUS-COERULEUS NEURONS

The effects of the proadrenomedullin N-terminal 20-amino acid peptide (PAMP) on the nicotinic acetylcholine (ACh) receptor (nAChR)-mediated inward current were investigated in neurons acutely dissociated from t he rat locus coeruleus using whole-cell recording under voltage clamp. Nicotine and cytidine mimicked the ACh response, whereas the maximal response to dimethyl-phenylpiperazinium was lower in amplitude compare d with that to ACh. Nicotine-induced current (I-nic) was suppressed mo re effectively by mecamylamine than by hexamethonium. In addition, nei ther atropine nor alpha-bungarotoxin affected the I-nic. PAMP reversib ly and noncompetitively suppressed the peak amplitude of 10(-4) M I-ni c. PAMP concentrations for the threshold, half-maximal inhibition, and maximal inhibition of 10(-4) M I-nic were 10(-8), 2.6 x 10(-7), and 1 0(-5) M, respectively, The peak amplitudes of 10(-4) M I-nic elicited at 2-min intervals showed a gradual decline in the presence of 10(-7) M PAMP. This decline in the I-nic was independent of the period of PAM P pretreatment. The suppression of I-nic by PAMP did not show any volt age dependency at a holding potential (V-H) of <0 mV, although the inh ibitory effect was masked by the marked inward rectification of I-nic at a V-H of >0 mV. These results suggest that PAMP could thus be a uni que endogenous peptide that antagonizes the nAChR in the CNS.