Inhibition of human platelet adenylate cyclase activity by adrenaline, thrombin and collagen: analysis and reinterpretation of experimental data.
Mathematical models based on the current understanding of stimulation and inhibition of adenylate cyclase (AC) activity have been developed and used to analyse experimental data [Farndale, Winkler, Martin and Barnes (1992) Biochem. J. 282, 2532] describing the inhibition of human platelet AC by collagen, thrombin and adrenaline. Here it has been demonstrated that neither affinities of receptors specific for adrenaline or thrombin nor the activity of cAMP phosphodiesterase are affected by collagen. Both collagen and thrombin at high doses act as effective inhibitors of AC activity. Inhibition of AC activity by collagen proceeds via two parallel pathways; the same is true for thrombin at moderate concentrations, and the two ligands act independently. The G-protein-dependence of these pathways is distinct from that mediating inhibition of AC activity by adrenaline, i.e. Gi2. Convergence of the inhibitory pathways takes place at the catalytic subunit of AC.
Juska
A
A
Biochemijos Institutas, Mokslininku 12, LT-2600 Vilnius, Lithuania. Alfonsas@bchi.lt
Farndale
R W
RW
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000527:Alprostadil / Q000494:pharmacology; D000704:Analysis of Variance; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D020134:Catalytic Domain; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000378:metabolism / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D011108:Polymers / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D013816:Thermodynamics; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
D000067956:Adenylyl Cyclase Inhibitors; D011108:Polymers; D011956:Receptors, Cell Surface; D003094:Collagen; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D013917:Thrombin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D000527:Alprostadil; D004837:Epinephrine