CALCITONIN-GENE-RELATED PEPTIDE ACTS PRESYNAPTICALLY TO INCREASE QUANTAL SIZE AND OUTPUT AT FROG NEUROMUSCULAR-JUNCTIONS

1. Calcitonin gene-related peptide (CGRP) is found in dense-cored vesi cles in the motor nerve terminal. 2. Exogenous CGRP increased the size of the quanta. The increase in size reached a maximum after about 40 min. The lowest effective concentration of human CGRP (hCGRP) was 0.8 nM. The action of hCGRP was antagonized by (-)-vesamicol, a drug that blocks active acetylcholine (ACh) uptake into synaptic vesicles, so it appears that hCGRP increases size by adding more ACh to the quanta. T he action of hCGRP was antagonized by drugs that block the activation of protein kinase A (PKA). (In other preparations CGRP also activates PKA.) 3. The hCGRP effect was not blocked by fragment 8-37, an antagon ist of one class of CGRP receptor. 4. hCGRP increases evoked quantal o utput and miniature endplate potential (MEPP) frequency, again by acti vating PKA. 5. CGRP release was measured by radioimmunoassay. Release was increased by depolarization with elevated K+, but the amounts rele ased appear to be below those needed to affect quantal size or output. Moreover, although elevated K+ can increase quantal size it acts by a pathway that does not involve PKA. We suggest that the most likely ta rget of endogenously released CGRP is the regulation of circulation of the muscle.