CARDIAC SARCOLEMMAL NA CA-INHIBITING PEPTIDES XIP AND FMRFAMIDE ALSO INHIBIT NA/CA EXCHANGE IN SQUID AXONS/

The effect of two cardiac sarcolemmal inhibitory peptides, the 20-amin o acid exchange inhibitory peptide (XIP) and the molluscan cardioexcit atory tetrapeptide amide Phe-Met-Arg-Phe-NH2 (FMRFa), were tested in d ialyzed squid giant axons. XIP injected into axons causes a maximal in hibition of 52 +/- 8% (n = 6) in the external Na (Na-0)-dependent Ca e fflux. The inhibitory effect was the same in axons dialyzed with satur ating intracellular Ca (Ca-i) concentration (100 mu M) and no MgATP or in axons containing submicromolar Ca-i concentrations (0.7 mu M) and 2 mM MgATP. FMRFa, a peptide that shows no obvious homology with XIP, also causes a marked inhibition in Na-0-dependent Ca efflux. As in car diac sarcolemmal vesicles, the peptide inhibits with low apparent affi nity (K-i = 1.9 mM; n = 5). Like XIP, FMRFa has the same effect in axo ns dialyzed with or without MgATP. The data indicate that XIP, which r esembles an endogenous calmodulin binding site that may have an autore gulatory function, and the tetrapeptide FMRFa, which binds to a putati ve opiate site, both inhibit Na/Ca exchange in squid axons. The sites at which these peptides bind are not related to the nucleotide (MgATP) regulation of Na/Ca exchange. We therefore suggest that these two sit es in the vertebrate cardiac Na/Ca exchange are conserved in the inver tebrate axon exchanger.