Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart.
Human heart failure is associated with a diminished contractile response to beta-adrenergic agonists. We hypothesized that alterations in the activity of a guanine nucleotide-binding regulatory protein (G protein) might be partially responsible for this abnormality. We therefore measured the activity of G proteins in failing human myocardium utilizing bacterial toxin-catalyzed ADP ribosylation. The activity of a 40,000-mol wt pertussis toxin substrate (alpha G40) was increased by 36% in failing human hearts when compared with nonfailing controls. In contrast, there was no change in the level of the stimulatory regulatory subunit (Gs). The increased activity in alpha G40 was associated with a 30% decrease in basal as well as 5'-guanylyl imidodiphosphate-stimulated adenylate cyclase activity. These data suggest that increased alpha G40 activity is a new marker for failing myocardium and may account at least in part for the diminished responsiveness to beta 1-adrenergic agonists in the failing human heart.
Feldman
A M
AM
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Cates
A E
AE
Veazey
W B
WB
Hershberger
R E
RE
Bristow
M R
MR
Baughman
K L
KL
Baumgartner
W A
WA
Van Dop
C
C
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000201:enzymology / Q000378:metabolism*; D002384:Catalysis; D002648:Child; D002772:Cholera Toxin / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000378:metabolism; D037342:Pertussis Toxin; D010761:Phosphorus Radioisotopes; D011943:Receptors, Adrenergic, beta / Q000032:analysis; D013379:Substrate Specificity; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D037361:Adenylate Cyclase Toxin; C029152:G-substrate; D009419:Nerve Tissue Proteins; D010761:Phosphorus Radioisotopes; D011943:Receptors, Adrenergic, beta; D010566:Virulence Factors, Bordetella; D000246:Adenosine Diphosphate Ribose; D002772:Cholera Toxin; D037342:Pertussis Toxin; D003402:Creatine Kinase; D000262:Adenylyl Cyclases