Truncated somatostatin receptors as new players in somatostatin-cortistatin pathophysiology.

Somatostatin (SST) and cortistatin (CORT) act through a family of seven transmembrane domain (TMD) receptors (sst1-5) to govern multiple functions, from growth hormone (GH) secretion to neurotransmission, metabolic homeostasis, gastrointestinal and immune function, and tumor cell growth. Thus, SST analogs are used to treat endocrine/tumoral pathologies. Yet, some SST/CORT actions cannot be explained by their interaction with known ssts. We recently identified novel sst5 variants in human, pig, mouse, and rat that lack one or more TMDs and display unique molecular/functional features: they exhibit distinct tissue distribution, divergent responses to SST/CORT, and intracellular localization as opposed to the typical plasma-membrane distribution of full-length ssts. When coexpressed in the same cell, truncated sst5 variants colocalize and physically interact with full-length ssts, providing a molecular basis to disrupt normal sst2/sst5 functioning. This may explain the inverse correlation between hsst5TMD4 expression in pituitary tumors and octreotide responsiveness in acromegaly. Discovery of these new truncated sst5 variants provides novel insights on SST/CORT/sst pathophysiology and suggests new research avenues for the therapeutic potential of this system.