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Volume 272, Number 30, Issue of July 25, 1997 pp. 18666-18672
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Both Overlapping and Distinct Signaling Pathways for Somatostatin Receptor Subtypes SSTR1 and SSTR2 in Pituitary Cells

(Received for publication, March 17, 1997, and in revised form, May 12, 1997)

Longchuan Chen , V. Danial Fitzpatrick ^§ , Richard L. Vandlen ^§ and Armen H. Tashjian Jr.

From the  Department of Molecular and Cellular Toxicology, Harvard School of Public Health, and the  Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 and the ^§ Department of Protein Chemistry, Genentech, Inc., South San Francisco, California 94080

To elucidate the signaling events mediated by specific somatostatin receptor (SSTR) subtypes, we expressed SSTR1 and SSTR2 individually in rat pituitary GH₁2C₁ and F₄C₁ cells, which lack endogenous somatostatin receptors. In transfected GH₁2C₁ cells, both SSTR1 and SSTR2 coupled to inhibition of Ca²⁺ influx and hyperpolarization of membrane potential via a pertussis toxin (PTx)-sensitive mechanism. These effects reflected modulation of ion channel activities which are important for regulation of hormone secretion. Somatostatin analogs MK678 and CH275 acted as subtype selective agonists as expected. In transfected F₄C₁ cells, both SSTR1 and SSTR2 mediated somatostatin-induced inhibition of adenylyl cyclase via a PTx-sensitive pathway. In addition, activation of SSTR2 in F₄C₁ cells, but not SSTR1, stimulated phospholipase C (PLC) activity and an increase in [Ca²⁺]_i due to release of Ca²⁺ from intracellular stores. Unlike adenylyl cyclase inhibition, the PLC-mediated response was only partially sensitive to PTx. To determine the structural determinants in SSTR2 necessary for activation of PLC, we constructed chimeric receptors in which domains of SSTR2 were introduced into SSTR1. Chimeric receptors containing only the third intracellular loop, or all three intracellular loops from SSTR2, mediated inhibition of adenylyl cyclase, but failed to stimulate PLC activity as did wild-type SSTR2. Furthermore, the C-terminal tail of SSTR2 was not required for coupling to PLC. Thus, by expressing individual somatostatin receptor subtypes in pituitary cells, we have identified both overlapping and distinct signaling pathways for SSTR1 and SSTR2, and have shown that sequences other than simply the intracellular domains are required for SSTR2 to couple to the PLC signaling pathway.

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