Beta(2)-adrenergic and several other G protein-coupled receptors in human atrial membranes activate both G(s) and G(i).
Cardiac G protein-coupled receptors that couple to Galpha(s) and stimulate cAMP formation (eg, beta-adrenergic, histamine, serotonin, and glucagon receptors) play a key role in cardiac inotropy. Recent studies in rodent cardiac myocytes and transfected cells have revealed that one of these receptors, the beta(2)-adrenergic receptor (AR), also couples to the inhibitory G protein Galpha(i) (activation of which inhibits cAMP formation). If beta(2)ARs could be shown to couple to Galpha(i) in the human heart, it would have important ramifications, because levels of Galpha(i) increase with age and in failing human heart. Therefore, we investigated whether beta(2)ARs in the human heart activate Galpha(i). By photoaffinity labeling human atrial membranes with [(32)P]azidoanilido-GTP, followed by immunoprecipitation with antibodies specific for Galpha(i), we found that Galpha(i) is activated by stimulation of beta(2)ARs but not of beta(1)ARs. In addition, we found that other Galpha(s)-coupled receptors also couple to Galpha(i), including histamine, serotonin, and glucagon. When coupling of these receptors to Galpha(i) is disrupted by pertussis toxin, their ability to stimulate adenylyl cyclase is enhanced. These data provide the first evidence that beta(2)AR and many other Galpha(s)-coupled receptors in human atrium also couple to Galpha(i) and that abolishing the coupling of these receptors to Galpha(i) increases the receptor-mediated adenylyl cyclase activity.
Kilts
J D
JD
Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
Gerhardt
M A
MA
Richardson
M D
MD
Sreeram
G
G
Mackensen
G B
GB
Grocott
H P
HP
White
W D
WD
Davis
R D
RD
Newman
M F
MF
Reves
J G
JG
Schwinn
D A
DA
Kwatra
M M
MM
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000368:Aged; D020517:Atrial Appendage / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry; D004280:Dobutamine / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology; D037342:Pertussis Toxin; D019920:Photoaffinity Labels; D011233:Precipitin Tests; D018342:Receptors, Adrenergic, beta-1 / Q000032:analysis / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000032:analysis* / Q000378:metabolism; D018027:Receptors, Glucagon / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D019920:Photoaffinity Labels; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D011956:Receptors, Cell Surface; D018027:Receptors, Glucagon; D011968:Receptors, Histamine; D011985:Receptors, Serotonin; D010566:Virulence Factors, Bordetella; D004280:Dobutamine; C002904:zinterol; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D007545:Isoproterenol