Murine ventricular L‐type Ca 2+ current is enhanced by zinterol via β 1 ‐adrenoceptors, and is reduced in TG4 mice overexpressing the human β 2 ‐adrenoceptor

The functional coupling of β 2 ‐adrenoceptors (β 2 ‐ARs) to murine L‐type Ca 2+ current (I Ca(L) ) was investigated with two different approaches. The β 2 ‐AR signalling cascade was activated either with the β 2 ‐AR selective agonist zinterol (myocytes from wild‐type mice), or by spontaneously active, unoccupied β 2 ‐ARs (myocytes from TG4 mice with 435 fold overexpression of human β 2 ‐ARs). Ca 2+ and Ba 2+ currents were recorded in the whole‐cell and cell‐attached configuration of the patch‐clamp technique, respectively. Zinterol (10 μ M ) significantly increased I Ca(L) amplitude of wild‐type myocytes by 19±5%, and this effect was markedly enhanced after inactivation of Gi‐proteins with pertussis‐toxin (PTX; 76±13% increase). However, the effect of zinterol was entirely mediated by the β 1 ‐AR subtype, since it was blocked by the β 1 ‐AR selective antagonist CGP 20712A (300 n M ). The β 2 ‐AR selective antagonist ICI 118,551 (50 n M ) did not affect the response of I Ca(L) to zinterol. In myocytes with β 2 ‐AR overexpression I Ca(L) was not stimulated by the activated signalling cascade. On the contrary, I 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 Ca(L) . The β 2 ‐AR inverse agonist ICI 118,551 did not further decrease I Ca(L) . PTX‐treatment increased current amplitude to values found in control myocytes. In conclusion, there is no evidence for β 2 ‐AR mediated increases of I Ca(L) in wild‐type mouse ventricular myocytes. Inactivation of Gi‐proteins does not unmask β 2 ‐AR responses to zinterol, but augments β 1 ‐AR mediated increases of I Ca(L) . In the mouse model of β 2 ‐AR overexpression I Ca(L) is reduced due to tonic activation of Gi‐proteins.British Journal of Pharmacology (2001) 133 , 73–82; doi: 10.1038/sj.bjp.0704045