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ACh-induced rebound stimulation of L-type Ca²⁺ current in guinea-pig ventricular myocytes, mediated by G-dependent activation of adenylyl cyclase

Andriy E. Belevych, Carl Sims and Robert D. Harvey

1. The effects that muscarinic receptor stimulation have on the cAMP-dependent regulation of L-type Ca²⁺ currents were studied in isolated guinea-pig ventricular myocytes using the whole-cell configuration of the patch-clamp technique.
2. The muscarinic agonist ACh inhibited the Ca²⁺ current stimulated by the -adrenergic agonist isoprenaline (Iso), and washout of ACh revealed a stimulatory response that appeared as a transient rebound increase in the amplitude of the Ca²⁺ current. The ACh-induced stimulatory effect was not observed in the absence of Iso.
3. ACh-induced rebound stimulation was also observed in the presence of H₂ histamine receptor activation and cholera toxin treatment, which like -adrenergic receptor activation enhance adenylyl cyclase (AC) activity in a stimulatory G protein (G_s)-dependent manner. ACh-induced rebound stimulation was not observed in the presence of forskolin, which enhances AC activity in a G_s-independent manner.
4. Pertussis toxin (PTX) treatment blocked both the stimulatory and inhibitory effects of ACh. Intracellular dialysis with QEHA, a peptide that binds free G protein subunits, selectively antagonized the stimulatory effect, leaving an enhanced inhibitory effect.
5. Evidence for the expression of AC4, an isoform of AC that can be stimulated by G but only in the presence of G_s, was obtained by Western blot analysis of guinea-pig ventricular myocyte membrane preparations.
6. These results suggest that muscarinic receptor stimulation facilitates as well as inhibits cAMP-dependent regulation of the Ca²⁺ current and that the net response is a balance between these two actions. We suggest that the stimulatory effect is due to a direct activation of AC4 by the subunits of a PTX-sensitive G protein.

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