A functional comparison of recombinant and native somatostatin sst 2 receptor variants in epithelia

Abstract

Background and purpose. Somatostatin (SRIF-14) exerts broad spectrum antisecretory effects by activating the somatostatin 2 (sst 2) receptor. The rat (r) sst 2 receptor exists in 'long' (sst 2a) and 'short' (sst 2b) forms that differ in their C termini, while a single human (h) sst 2a exists. This study compares the characteristics of recombinant rsst 2a, rsst 2b and hsst 2a activation in human epithelia, and with native sst 2 responses in rat colon. Experimental approach. Epithelial layers of each clone or rat colon were placed in Ussing chambers and short-circuit current (I SC) measured in response to SRIF-14 and chosen analogues. The relative potencies and ability to cause desensitization to SRIF-14 were assessed, and the affinities of the sst 2 antagonist, D-Tyr 8 CYN154806 for hsst 2a, rsst 2a and native rat colon sst 2 receptors were established. Key results. Basolateral SRIF-14 responses were transient in hsst 2a and rsst 2a epithelia, but prolonged in rsst 2b-expressing cells. Activation of rsst 2a resulted in significant desensitization to SRIF-14 and receptor phosphorylation, whereas the rsst 2b receptor did neither. Sst 2-preferred agonists (BIM23190C and BIM23027) reduced I sc with similar potency and both caused complete desensitization to SRIF-14. CYN154806 antagonized hsst 2a and rsst 2a receptors with pK B values of 7.9 and 7.8, respectively. In rat colon mucosa, CYN154806 blocked SRIF-14 responses with a pA 2 value of 8.2, and BIM23190C responses with a pK B of 8.4. Conclusions and implications. SRIF-14 caused rapid rsst 2a receptor phosphorylation and desensitization of epithelial antisecretory responses, neither of which occurred with the rsst 2b receptor. These mechanisms are most likely to be a prerequisite for sensitivity to sst 2-analogues with radiotherapeutic potential. © 2007 Nature Publishing Group All rights reserved.