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Subtype-specific signaling mechanisms of somatostatin receptors SSTR1 and SSTR2.

1994; Elsevier BV; Volume: 269; Issue: 14 Linguagem: Inglês

10.1016/s0021-9258(17)34068-1

1083-351X

Chuan Hou, Richard Gilbert, Diane L. Barber,

Receptor Mechanisms and Signaling

Somatostatin regulates diverse cellular effectors, including adenylyl cyclase, ion channels, and ion exchangers.We expressed two somatostatin receptor subtypes, SSTRl and SSTR2, stably in mouse fibroblast Ltk-cells and transiently in human embryonic kidney HEK293 cells to investigate subtype-specific pharmacological and functional properties.The effects of GTP* and pertussis toxin on [1asI-'&r11]somatostatin-14 binding indicated that SST= may couple exclusively to pertussis toxin-sensitive G proteins, whereas SSTRl may couple to both pertussis-sensitive and -insensitive G proteins.When expressed either stably or transiently, both receptor subtypes mediated somatostatin inhibition of CAMP accumulation by a pertussis toxin-sensitive mechanism.In contrast, only SSTRl mediated somatostatin inhibition of Na+-H' exchange activity, and this action was insensitive to pertussis toxin.We generated two chimeric receptors by replacing sequential residues of SSTR2 with cognate sequences of SSTRl to identify molecular determinants unique to SSTRl that may confer coupling to the exchanger.SSTCR4 included a SSTRl segment encompassing determinants within the fifth and sixth hydrophobic domains and the entire third cytoplasmic loop, while SSTCRS contained a SSTRl segment spanning the second through sixth hydrophobic domains, including both second and third cytoplasmic loops.Although both chimeric receptors mediated somatostatin inhibition of CAMP accumulation, only SSTCRS mediated the inhibition of Na+-H+ exchange activity, and this effect was pertussis-insensitive.These findings demonstrate both pharmacological and functional differences between SSTRl and SSTR2.The ability of SSTRl to selectively attenuate Na+-H+ exchange activity requires determinants outside the third cytoplasmic domain.The tetradecapeptide somatostatin is expressed throughout the gastrointestinal tract as well as the peripheral and central nervous systems.The general inhibitory action of somatostatin is mediated through its interaction with specific membranebound somatostatin receptors that are coupled to multiple cellular effector pathways.Somatostatin receptors inhibit adenylyl cyclase (l), voltage-dependent Ca2+ channels (2), and the mobilization of intracellular Ca2+ (3).Somatostatin receptors also stimulate voltage-dependent K+ channels (4) and protein phosphatases ( 5 , 6 ) .Although many effects of somatostatin oc-