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A functional comparison of recombinant and native somatostatin sst 2 receptor variants in epithelia
Author(s) -
Holliday N D,
Tough I R,
Cox H M
Publication year - 2007
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707365
Subject(s) - medicine , somatostatin , endocrinology , agonist , somatostatin receptor , receptor , somatostatin receptor 2 , desensitization (medicine) , antagonist , biology , chemistry
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 p K B values of 7.9 and 7.8, respectively. In rat colon mucosa, CYN154806 blocked SRIF‐14 responses with a p A 2 value of 8.2, and BIM23190C responses with a p K 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. British Journal of Pharmacology (2007) 152 , 132–140; doi: 10.1038/sj.bjp.0707365