Adenosine A1 receptor-induced upregulation of protein kinase C: role of pertussis toxin-sensitive G protein(s).
Biochemical and pharmacological studies have established that adenosine modulates protein kinase C (PKC), which plays an important role in the maintenance of vascular tone. Our earlier studies [Marala and Mustafa. Am. J. Physiol. 268 (Heart Circ. Physiol. 37): H271-H277, 1995. Marala, R. B., K. Ways, and S. J. Mustafa. Am. J. Physiol. 264 (Heart Circ. Physiol. 33): H1465-H1471, 1993] have shown the involvement of adenosine A1 receptors and not the A2 receptors in the upregulation of PKC in porcine coronary artery. The mechanism(s) by which adenosine upregulates PKC is not yet clearly understood. We now report the increased expression of PKC by adenosine A1 receptor through an upstream activation of pertussis toxin-sensitive G protein(s). Incubation of porcine coronary artery for 24 h with a relatively specific A1-receptor agonist (2S)-N6-(2-endo-norbornyl)adenosine (ENBA) elevated the contractile responses to endothelin-1 by about twofold, probably due to an increased expression of PKC. Incubation of porcine coronary artery with ENBA also protected against the phorbol 12,13-dibutyrate (PDBu)-induced depletion of PKC. Inclusion of pertussis toxin in the incubation medium completely blocked both the upregulatory and the protective effects of ENBA. Incubation with pertussis toxin did not alter the PKC activity as judged by the contractile responses to PDBu. On the contrary, incubation of porcine coronary artery with cholera toxin for 24 h did not alter any of the ENBA responses (upregulation of PKC and the protection against PDBu-induced PKC depletion). Incubation conditions of coronary arteries with toxins are sufficient to cause ADP ribosylation of respective G proteins as judged by back ADP ribosylation studies.(ABSTRACT TRUNCATED AT 250 WORDS)
Marala
R B
RB
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, North Carolina 27858, USA.
Mustafa
S J
SJ
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D002772:Cholera Toxin / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology*; D008297:Male; D009636:Norbornanes / Q000494:pharmacology; D037342:Pertussis Toxin; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D013552:Swine; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
C089285:N(6)-(2-endo-norbornyl)adenosine; D009636:Norbornanes; D018047:Receptors, Purinergic P1; D010566:Virulence Factors, Bordetella; D000246:Adenosine Diphosphate Ribose; D015240:Phorbol 12,13-Dibutyrate; D002772:Cholera Toxin; D037342:Pertussis Toxin; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D000241:Adenosine