The cellular mechanisms by which sstr2 may mediate the inhibition of GH release are not established. However, the cellular responses linked to this receptor have been identified. sstr2 couples to adenylyl cyclase and mediates inhibition of cAMP formation induced by SRIF (1,23). The cloned sstr2 has been reported to couple to voltage-sensitive Ca2+ channels and mediate inhibition of Ca2+ influx (24). Recent studies have also shown that sstr2 selective ligands can inhibit an L-type Ca2+ channel in AtT-20 cells to block Ca2+ influx (25). In these cells, some sstr2 analogs, such as BIM 23027 and MK 678 potentiate a K+ current via an inwardly rectifying K+ channel (26). However, the pharmacology of this effect is not consistent with a role of sstr2, because octapeptide analogs that are selective for sstr2, such as NC8-12 and octreotide, have no effect on this current. Furthermore, the ability of SRIF to potentiate this K+ current is blocked by the peptide developed by Coy and his associates (17,18), referred to as the somatostatin antagonist. This peptide has no affinity for sstr2 (14) indicating that the SRIF receptor linked to the K+ current in AtT-20 cells is a receptor that has not been cloned. These studies suggest that either inhibition of cAMP accumulation or Ca2+ influx are the major mechanisms by which sstr2 is likely to mediate inhibitory effects of SRIF on GH release.
SRIF receptors are linked to these diverse cellular effector systems via G proteins (1,27). Biochemical studies have revealed that SRIF receptors in brain and AtT-20 cells are capable of coupling to Gia1, Gia3, and Goa (27-31). Functional studies have revealed that these different G proteins can link SRIF receptors to different cellular effector systems. Gia1 was reported to couple SRIF receptors to adenylyl cyclase (32). Gia3 has been shown to link SRIF receptors to K+ channels (33) and Goa mediates SRIF's inhibition of Ca2+ currents (34). By acting through different G proteins, SRIF can independently regulate each effector system.
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