PKC-independent inhibition of cardiac L-type Ca2+ channel current by phorbol esters.
Active and inactive phorbol esters were applied to guinea pig ventricular myocytes to study the responses of L-type Ca2+ (ICa,L) and L-type Na+ (INa,L) currents. Phorbol 12-myristate 13-acetate (PMA) (10-100 rM) never stimulated ICa,L or INa,L and frequently depressed them by 5-30% in a voltage-independent manner. However, the phorbol ester consistently activated delayed-rectifying K+ (IK) and Cl- currents. The inhibition of ICa,L occurred approximately 3 times faster than comonitored stimulation of IK, and ICa,L and INa,L were unaffected by two interventions that suppressed IK stimulation [pretreatment with 50 microM 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) and dialysis with pCa 11 versus standard pCa 9 solution]. Inactive phorbol esters 4 alpha-phorbol 12,13-didecanoate (alpha-PDD) and 4 alpha-phorbol had little effect on IK, but alpha-PDD had a PMA-like inhibitory effect on Ca2+ channel currents. We conclude that, unlike the stimulation of IK by PMA, inhibition of Ca2+ channel current by phorbol esters is a protein kinase C-independent action.
Asai
T
T
Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
Shuba
L M
LM
Pelzer
D J
DJ
McDonald
T F
TF
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology*; D004553:Electric Conductivity; D006168:Guinea Pigs; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013997:Time Factors
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D015221:Potassium Channels; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate