ABSTRACT
Somatostatin (SST) was originally isolated from the hypothalamus as the key suppressor GH secretion, but is now known to be widely distributed throughout the body and to be involved in numerous physiological functions. While the varied activity of SST creates opportunities for its use as a therapeutic agent, it also hampers drug development by creating the potential for inducing undesired actions. The discovery of five distinct somatostatin recep tor (SSTR) subtypes has provided an opportunity for creating subtype-specific, and, poten tially, action-specific SST analogs. Through efforts to determine the functional association between receptor subtype and function, it has become apparent that most SST-responsive target tissues express multiple receptor subtypes, and that it is the interaction of the subtypes that will determine the cellular response. In this regard, we have observed both action-enhancing and antagonistic interactions between different SSTR subtype combinations, and that these effects can be induced in a gradated fashion depending on the degree to which the different subtypes present are activated. These observations imply that the cellular response to SST is dictated by the ratio of receptor subtypes present on the cell at a given moment. In this way, the cellular response to SST can be influenced by the prevailing environmental conditions, physi ological status and hormonal milieu, through alteration of the ratio of receptor subtypes ex pressed. One can also envision the development of pathologies in which the cellular response is inappropriate due to altered ratios of receptor subtype expression. The concept of receptor interaction attains even greater complexity with the demonstration that the SSTR subtypes can also interact with members of other receptor families. These complex interactions provide po tential opportunities for creating drugs that target only specific combinations of receptors that are expressed under the appropriate conditions to generate a specific cellular response. Learn ing to unravel this complex cellular code is key, both for furthering our understanding of cellular based physiology and disease, and in order to create more effective drugs with greater functional specificity.
