INHIBITORY PATHWAY OF CARDIAC PKA-DEPENDENT CL- CONDUCTANCE VIA PERTUSSIS-TOXIN-SENSITIVE G-PROTEINS

The inhibitory pathway of cardiac cAMP-dependent protein kinase-regula ted Cl- conductance was investigated using the whole-cell configuratio n of patch-clamp techniques in single guinea pig ventricular myocytes. Pertussis toxin-sensitive G proteins (G(i)), mediating the signal tra nsductions between muscarinic receptors and adenylate cyclase, have a substantial tonic activity even in the absence of muscarinic receptor modulators. Muscarinic agonists or antagonists (like atropine) either increase or decrease this basal activity of G(i) by altering the propo rtion of active and inactive forms of the receptors. Similar to L-type Ca-channel currents, the Cl- conductance showed a transient over-reco very upon cessation of brief muscarinic receptor stimulation by carbac hol (CCh) (rebound). Atropine alone enhanced the Cl- conductance elici ted by low concentrations of Iso (reverse agonist). After washout of a tropine, the over-suppression of the conductance was observed as a mir ror image of CCh-induced rebound (reverse rebound). Both types of rebo und became prominent when cell dialysis with pipette solutions contain ing 100 mu M GTP was minimized with high-resistance pipettes. Endogeno us GTP is therefore an intracellular modulator, and not simply a media tor, of G(i)-dependent signal transduction.