Heparin and other polyanions uncouple alpha 1-adrenoceptors from G-proteins.
Several polyanionic compounds antagonize the interaction between receptors and the G-proteins that regulate adenylate cyclase or K+ channels, possibly by binding to a basic stretch of the receptor that is proposed to mediate its interaction with the G-proteins. We have studied the effects of polyanions on the interaction between the liver alpha 1-adrenoceptor and the G-protein through which it stimulates polyphosphoinositide turnover. Heparin [concn. causing 50% of maximal effect (EC50) = 0.5 microM], Trypan Blue (EC50 7.1 microM) or suramin (EC50 2.1 microM) prevented formation of the high-affinity adrenaline-receptor-G-protein complex without affecting antagonist binding. After alkaline treatment of the membranes, previously reported to cause G-protein removal, binding of agonists was insensitive to both guanine nucleotides and heparin. We conclude that these polyanions uncouple the alpha 1-adrenoceptor from its G-protein, suggesting that similar coupling mechanisms may underlie receptor activation of the G-proteins that activate polyphosphoinositide hydrolysis and those that regulate adenylate cyclase. This action of heparin severely limits its utility as a selective antagonist of the Ins(1,4,5)P3 receptor in intact cells.
Dasso
L L
LL
Department of Pharmacology, University of Cambridge, U.K.
Taylor
C W
CW
D037361:Adenylate Cyclase Toxin; D000818:Animals; D000838:Anions / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D004837:Epinephrine / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology*; D008297:Male; D010646:Phentolamine / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011224:Prazosin / Q000378:metabolism; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism*; D013498:Suramin / Q000378:metabolism; D014343:Trypan Blue / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella
D037361:Adenylate Cyclase Toxin; D000838:Anions; D011942:Receptors, Adrenergic, alpha; D014475:Uncoupling Agents; D010566:Virulence Factors, Bordetella; D013498:Suramin; D006160:Guanosine Triphosphate; D006493:Heparin; D010727:Phosphoric Diester Hydrolases; C021491:glycerophosphoinositol glycerophosphodiesterase; D019204:GTP-Binding Proteins; D014343:Trypan Blue; D011224:Prazosin; D004837:Epinephrine; D010646:Phentolamine