Regulation of the extracellular signal-regulated kinase pathway in adult myocardium: differential roles of G(q/11), Gi and G(12/13) proteins in signalling by alpha1-adrenergic, endothelin-1 and thrombin-sensitive protease-activated receptors.
Using adenoviruses encoding RGS2, RGS4 and Lsc (regulator of G protein signalling (RGS) domain of p115 RhoGEF), we investigated the contributions of G(q/11), Gi and G(12/13) proteins to G protein-coupled receptor (GPCR)-mediated activation of the extracellular signal-regulated kinase (ERK) pathway in adult rat ventricular myocytes (ARVM). Exposure to phenylephrine, endothelin-1 (ET-1) or thrombin induced significant activation of ERK1/2 and their downstream target 90 kDa ribosomal S6 kinase (p90RSK), which was abolished by overexpression of RGS4 (inhibits signalling via G(q/11) and Gi) or RGS2 (inhibits signalling via G(q/11)). Pertussis toxin (inhibits signalling via Gi) only partially attenuated the activation of ERK1/2 and p90(RSK) by phenylephrine and ET-1, but abolished such activation by thrombin. Overexpression of Lsc (inhibits signalling via G(12/13)) did not affect the responses to phenylephrine and ET-1, but suppressed the activation of ERK1/2 and p90RSK by thrombin. We conclude that full activation of the ERK pathway in ARVM by alpha1-adrenergic, ET-1 and thrombin receptors requires the activation of distinct families of heterotrimeric G proteins.
Snabaitis
Andrew K
AK
Cardiovascular Division, King's College London, The Rayne Institute, St Thomas' Hospital, London, SE1 7EH, United Kingdom.
Muntendorf
Andreas
A
Wieland
Thomas
T
Avkiran
Metin
M
D000256:Adenoviridae / Q000235:genetics; D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D044385:GTP-Binding Protein alpha Subunits / Q000502:physiology*; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology; D005822:Genetic Vectors; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry; D020935:MAP Kinase Signaling System; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D044385:GTP-Binding Protein alpha Subunits; D020662:Guanine Nucleotide Exchange Factors; D020710:RGS Proteins; D044022:Receptor, Endothelin A; D018340:Receptors, Adrenergic, alpha-1; D043562:Receptors, G-Protein-Coupled; D018179:Receptors, Thrombin; D064067:Rho Guanine Nucleotide Exchange Factors; C098799:RGS4 protein; D010656:Phenylephrine; D037342:Pertussis Toxin; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11