Background and purpose.Somatostatin (SRIF‐14) exerts broad spectrum antisecretory effects by activating the somatostatin 2 (sst2) receptor. The rat (r) sst2 receptor exists in ‘long’ (sst2a) and ‘short’ (sst2b) forms that differ in their C termini, while a single human (h) sst2a exists. This study compares the characteristics of recombinant rsst2a, rsst2b and hsst2a activation in human epithelia, and with native sst2 responses in rat colon.Experimental approach.Epithelial layers of each clone or rat colon were placed in Ussing chambers and short‐circuit current (ISC) 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 sst2 antagonist, D‐Tyr8 CYN154806 for hsst2a, rsst2a and native rat colon sst2 receptors were established.Key results.Basolateral SRIF‐14 responses were transient in hsst2a and rsst2a epithelia, but prolonged in rsst2b‐expressing cells. Activation of rsst2a resulted in significant desensitization to SRIF‐14 and receptor phosphorylation, whereas the rsst2b receptor did neither. Sst2‐preferred agonists (BIM23190C and BIM23027) reduced Isc with similar potency and both caused complete desensitization to SRIF‐14. CYN154806 antagonized hsst2a and rsst2a receptors with pKB values of 7.9 and 7.8, respectively. In rat colon mucosa, CYN154806 blocked SRIF‐14 responses with a pA2 value of 8.2, and BIM23190C responses with a pKB of 8.4.Conclusions and implications.SRIF‐14 caused rapid rsst2a receptor phosphorylation and desensitization of epithelial antisecretory responses, neither of which occurred with the rsst2b receptor. These mechanisms are most likely to be a prerequisite for sensitivity to sst2‐analogues with radiotherapeutic potential.British Journal of Pharmacology (2007) 152, 132–140; doi:10.1038/sj.bjp.0707365