Different domains in the third intracellular loop of the GLP-1 receptor are responsible for Galpha(s) and Galpha(i)/Galpha(o) activation.
It has previously been shown that the GLP-1 receptor is primarily coupled to the adenylate cyclase pathway via activation of Galpha(s) proteins. Recent studies have shown that the third intracellular loop of the receptor is important in the stimulation of cAMP production. We have studied the effect of three synthetic peptide sequences derived from the third intracellular loop of the GLP-1 receptor on signal transduction in Rin m5F cell membranes. The whole third intracellular loop strongly stimulates both pertussis toxin and cholera toxin-sensitive G proteins, while the N-terminal half exclusively stimulates cholera toxin-sensitive G proteins and the C-terminal half only stimulates pertussis toxin-sensitive G-proteins as demonstrated by measurements of GTPase activity. These data confirm that the principal stimulatory G-protein interaction site resides in the third intracellular loop, but also suggest that the GLP-1 receptor is not only coupled to the Galpha(s) but also to the Galpha(i)/Galpha(o) type of G proteins and that distinct domains within the third intracellular loop are responsible for the activation of the different G-protein subfamilies.
Hällbrink
M
M
Department of Neurochemistry and Neurotoxicity, Stockholm University, S-106 91 Stockholm, Sweden.
Holmqvist
T
T
Olsson
M
M
Ostenson
C G
CG
Efendic
S
S
Langel
U
U
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002772:Cholera Toxin; D000242:Cyclic AMP / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000737:chemistry*; D000067757:Glucagon-Like Peptide-1 Receptor; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000737:chemistry / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D037342:Pertussis Toxin; D011485:Protein Binding; D018027:Receptors, Glucagon / Q000737:chemistry* / Q000235:genetics; D015398:Signal Transduction; D010566:Virulence Factors, Bordetella
D037361:Adenylate Cyclase Toxin; D044385:GTP-Binding Protein alpha Subunits; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D010566:Virulence Factors, Bordetella; C084618:olfactory G protein subunit alpha olf; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D020558:GTP Phosphohydrolases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins; D000262:Adenylyl Cyclases