Secretagogue-induced Somatostatin Receptor Recruitment

In this study, we have correlated the translocation of somatostatin (SRIF) receptors from the cell interior to the plasma membrane with the ability of SRIF to inhibit insulin release. Islets were perifused with glucose (30, 100, 165, 200, or 300 mg/dl) in the presence of sodium isethionate. Sodium isethionate inhibits insulin release, but not the recruitment of SRIF receptors. Thus, the recruitment of SRIF receptors to the surface membrane continued without the lysis of secretion vesicles. SRIF binding rose from 3.75±0.16 to 6.46±0.28 fmol/ 10 islets as glucose concentration increased. Sodium isethionate was then removed, islets perifused with low glucose (30 mg/dl), and challenged with 400 gM isobutylmethylxanthine (IBMX) with or without SRIF (5 ,ug/ml). In the islets perifused with high glucose concentration, IBMX lysed a greater number of vesicles and caused enhanced release of insulin. The greater the number of secretion vesicles marginated to the plasma membrane by glucose, the greater the response to IBMX. Colchicine (1 mM) prevented secretion vesicle migration and this potentiation effect of higher concentrations of glucose was eliminated. In experiments with IBMX and SRIF, the degree of inhibition of IBMX-induced insulin release by SRIF was proportional to the magnitude of SRIF binding to these islets. SRIF inhibited insulin release by 20 gU/100 islets initially perifused with low glucose (30 mg/dl) and by 875 IAU/100 islets perifused with high glucose (300 mg/dl). The maximal effect of SRIF was observed when its binding reached a level of 5.4 fmol/10 islets. We conclude that inhibition of insulin release by SRIF is proportional to the SRIF receptor concentration, and that translocation of SRIF receptors during exocytosis plays an important role in paracrine regulation of insulin secretion by rendering the islets more sensitive to SRIF. Introduction We have recently shown that glucose and sulfonylurea agents augment somatostatin (SRIF)' binding in isolated pancreatic This work was presented in part at the Annual Meeting of the American Diabetes Association, Las Vegas, NV, 10-12 June 1984. Address reprint requests to Dr. B. Draznin, Veterans Administration Medical Center, 1055 Clermont St., Denver, CO 80220. Receivedfor publication 2 July 1984 and in revisedform 24 January 1985. 1. Abbreviations used in this paper: AIR, acute insulin release; IBMX, isobutylmethylxanthine; NaIs, sodium isethionate; SRIF, somatostatin. islets concomitantly with the stimulation of insulin release (1). This enhancement in SRIF binding appears to be due to an increase in SRIF receptor concentration without a change in receptor affinity (1-3). Moreover, the bulk of SRIF receptors (80-87%) was found intracellularly, primarily in association with secretion vesicles (3-5). We have suggested that the secretion vesicle may provide the vehicle for translocating the receptor for SRIF from the cell interior to the plasma membrane during exocytosis (1, 2). We further proposed that an increase in SRIF binding following an initial burst of insulin release may render the islets more sensitive to SRIF's inhibition of insulin release. If this is true, this would represent a unique control mechanism in the paracrine regulation of hormone secretion. To test this hypothesis, we have examined the role of secretagogue-induced translocation of SRIF receptors to the plasma membrane in potentiating the biological action of SRIF in inhibiting insulin release.