BINDING-SITES FOR ISLET AMYLOID POLYPEPTIDE IN MAMMALIAN LUNG - SPECIES VARIATION AND EFFECTS ON ADENYLYL-CYCLASE

Islet amyloid polypeptide (IAPP) and calcitonin gene related peptide (CGRP) share a 47% sequence homology. LAPP can interact with adenylyl cyclase coupled CGRP receptors. We have examined [I-125]IAPP binding in mouse, pig, and guinea pig lung membranes in competition with IAPP, CORP, and CGRP(8-37). Three types of site were shown by order of potency: (i) mouse, IAPP > CGRP(8-37) much greater than CGRP; (ii) pig, CGRP > IAPP > CGRP(8-37); and (iii) guinea pig, CORP = IAPP = CGRP(8-37). Chemical cross-linking of [I-125]IAPP and [I-125]CGRP binding sites in lung demonstrated that both sites had similar molecular weights in any one species but differed across species, i.e., mouse M(r) = 70 000 and 98 000; pig M(r) = 68 000, 56 000, and 47 000; and guinea pig M(r) = 106 000 and 56 000. Adenylyl cyclase activity was stimulated by forskolin and A1Cl(3)-NaF in rat, mouse, pig, and guinea pig membranes. Only in mouse and pig were CORP and IAPP able to stimulate adenylyl cyclase activity. In mouse lung CGRP and LAPP stimulated adenylyl cyclase activity with EC(50) values of 642 +/- 222 nM (n = 4) and 325 +/- 115 nM (n = 4), respectively. In pig lung membranes EC(50) values were 5.7 +/- 0.3 nM (n = 4) for CGRP and 1230 +/- 1130 nM (n = 4) far IAPP. Thus IAPP either did not stimulate adenylyl cyclase activity in these lung membranes or did so with a low potency.