Role of the GTP-binding protein Gs in the β-adrenergic modulation of cardiac Ca channels

Cavalié, A., Allen, T. J. A. and Trautwein, W. 1991. Role of the GTP-binding protein Gs in the β-adrenergic modulation of cardiac Ca channels. Pflügers Archiv European Journal of Physiology 419 (5) , pp. 433-443. 10.1007/BF00370785

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Abstract

In the heart, the guanosine 5′-triphosphate (GTP)-binding protein Gs is activated by hormone binding to β-adrenergic receptors and stimulates the intracellular cyclic adenosine 3′,5′-monophosphate (cAMP) pathway that leads to phosphorylation of L-type Ca channels by the cAMP-dependent protein kinase A [28]. Additionally, Gs can modulate cardiac Ca channels directly in cell-free systems [57]. In order to examine the question of whether these pathways could be separated functionally and whether they act independently or synergistically on L-type Ca channels in intact cells, the whole-cell Ca current (ICa) and the respective current density were measured in guinea-pig ventricular myocytes at 0 mV. The following results were obtained. First, typically, the ICa density increased from 12 to 40 μA/cm2 following application of 1 μM isoproterenol (ISP) to myocytes bathed in solutions containing 1.8 mM CaCl2. However, 1 μM ISP enhanced ICa only from 9 to 17 μA/cm2 after inhibition of the protein kinase A by dialysis of 0.5 mM Rp-cAMPS (the Rp-isomer of adenosine 3′,5′-monophosphorothioate) in the presence of 0.5 mM GTP. Withdrawal of GTP from the dialysate attenuated the effects of ISP on ICa. Thus, Rpc-AMPS unmasks a GTP-dependent component of the β-adrenergic stimulation of ICa, which probably reflects the direct stimulation of Ca channels by Gs under block of cAMP-dependent phosphorylation. Second, in cells under dialysis with 100 or 200 μM cAMP, bath application of 20–40 μM 3-isobutyl-1-methylxanthine (IBMX) enhanced the ICa density to about 41 μA/cm2 indicating saturation of the cAMP pathway. Under this condition, 1 μM ISP was without significant effect on ICa. This result may suggests that direct Gs stimulation is rather ineffective on Ca channels after maximal cAMP-dependent phosphorylation. Alternatively, maximal stimulation of the cAMP pathway may also interfere with the activation of the Gs pathway in intact myocytes. Third, simultaneous application of 1 μM ISP and 40 μM IBMX enhanced ICa up to densities of around 75 μA/cm2 during cell dialysis with 100 μM cAMP, an effect much stronger than that exerted by IBMX alone under similar conditions. Since it seems likely that Gs is activated more quickly, than the cAMP pathway during application of the ISP/IBMX mixture, the latter result suggests that a direct effect of Gs may act to prime L-type Ca channels for cAMP-dependent phosphorylation during β-adrenergic stimulation of cardiac myocytes.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Springer Verlag (Germany)
ISSN:	0031-6768
Date of Acceptance:	19 July 1991
Last Modified:	15 Jan 2020 12:46
URI:	https://orca.cardiff.ac.uk/id/eprint/127189

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