Interaction of somatostatin receptors with G proteins and cellular effector systems.
Somatostatin induces its multiple biological actions by interacting with a family of receptors, referred to as sstr1-sstr5. To determine the molecular mechanisms of action of somatostatin, we have investigated the interaction of the different cloned receptors with G proteins and cellular effector systems. sstr2, sstr3 and sstr5 associate with pertussis toxin-sensitive G proteins and are able to mediate the inhibition of adenylyl cyclase activity by somatostatin. Two forms of sstr2, sstr2A and sstr2B, are generated by alternative splicing and differ in their C-terminal amino acid sequence. sstr2B couples to adenylyl cyclase whereas sstr2A does not. To investigate the basis for the differential coupling to adenylyl cyclase, we truncated sstr2B to the point of amino acid sequence divergence from sstr2A. The truncated sstr2B mediated the inhibition of cAMP formation by somatostatin, indicating that the C-terminus is not needed for coupling sstr2 to adenylyl cyclase. It is likely that the C-terminus of sstr2A hinders coupling to adenylyl cyclase. sstr2A associates with Gi alpha 3 and G(o) alpha but does not effectively interact with Gi alpha 1, a G protein that is necessary for coupling somatostatin receptors to adenylyl cyclase. The differential association of the splice variants with Gi alpha 1 may explain their contrasting effects on adenylyl cyclase activity. sstr3 also couples to adenylyl cyclase. Gi alpha 1 links sstr3 to adenylyl cyclase and mutagenesis studies have shown that the C-terminus of Gi alpha 1 is necessary for this coupling. The C-terminus of the Gi alpha proteins differ by only a few amino acid residues and only Gi alpha 1 couples sstr3 to adenylyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
Reisine
T
T
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Woulfe
D
D
Raynor
K
K
Kong
H
H
Heerding
J
J
Hines
J
J
Tallent
M
M
Law
S
S
D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D017481:Receptors, Somatostatin / Q000737:chemistry / Q000378:metabolism*; D017421:Sequence Analysis; D015398:Signal Transduction
D017481:Receptors, Somatostatin; D019204:GTP-Binding Proteins