Murine ventricular L-type Ca super(2+) current is enhanced by zinterol via beta sub(1)-adrenoceptors, and is reduced in TG4 mice overexpressing the human beta sub(2)-adrenoceptor

• Published in: British journal of pharmacology 2001-05, Vol.133 (1), p.73-82
• Main Authors: Heubach, J F, Graf, E M, Molenaar, P, Jaeger, A, Schroeder, F, Herzig, S, Harding, SE, Ravens, U
• Format: Article
• Language: English
• Subjects: b1-Adrenergic receptors; b2-Adrenergic receptors; zynterol
• ISSN: 0007-1188

The functional coupling of beta sub(2)-adrenoceptors ( beta sub(2)-ARs) to murine L-type Ca super(2+) current (I sub(Ca(L))) was investigated with two different approaches. The beta sub(2)-AR signalling cascade was activated either with the beta sub(2)-AR selective agonist zinterol (myocytes from wild-type mice), or by spontaneously active, unoccupied beta sub(2)-ARs (myocytes from TG4 mice with 435 fold overexpression of human beta sub(2)-ARs). Ca super(2+) and Ba super(2+) currents were recorded in the whole-cell and cell-attached configuration of the patch-clamp technique, respectively. Zinterol (10 mu M) significantly increased I sub(Ca(L)) amplitude of wild-type myocytes by 19 plus or minus 5%, and this effect was markedly enhanced after inactivation of Gi-proteins with pertussis-toxin (PTX; 76 plus or minus 13% increase). However, the effect of zinterol was entirely mediated by the beta sub(1)-AR subtype, since it was blocked by the beta sub(1)-AR selective antagonist CGP 20712A (300 nM). The beta sub(2)-AR selective antagonist ICI 118,551 (50 nM) did not affect the response of I sub(Ca(L)) to zinterol. In myocytes with beta sub(2)-AR overexpression I sub(Ca(L)) was not stimulated by the activated signalling cascade. On the contrary, I sub(Ca(L)) was lower in TG4 myocytes and a significant reduction of single-channel activity was identified as a reason for the lower whole-cell I sub(Ca(L)). The beta sub(2)-AR inverse agonist ICI 118,551 did not further decrease I sub(Ca(L)). PTX-treatment increased current amplitude to values found in control myocytes. In conclusion, there is no evidence for beta sub(2)-AR mediated increases of I sub(Ca(L)) in wild-type mouse ventricular myocytes. Inactivation of Gi-proteins does not unmask beta sub(2)-AR responses to zinterol, but augments beta sub(1)-AR mediated increases of I sub(Ca(L)). In the mouse model of beta sub(2)-AR overexpression I sub(Ca(L)) is reduced due to tonic activation of Gi-proteins.