β-Adrenoceptor/PKA-stimulation, Na+ –Ca2+ exchange and PKA-activated Cl− currents in rabbit cardiomyocytes: A conundrum

Abstract Investigations into the functional modulation of the cardiac Na+ –Ca2+ exchanger (NCX) by acute β-adrenoceptor/PKA stimulation have produced conflicting results. Here, we investigated (i) whether or not β-adrenoceptor activation/PKA stimulation activates current in rabbit cardiac myocytes under NCX-‘selective’ conditions and (ii) if so, whether a PKA-activated Cl− -current may contribute to the apparent modulation of NCX current ( INCX ). Whole-cell voltage-clamp experiments were conducted at 37 °C on rabbit ventricular and atrial myocytes. The β-adrenoceptor-activated currents both in NCX-‘selective’ and Cl− -selective recording conditions were found to be sensitive to 10 mM Ni2+ . In contrast, the PKA-activated Cl− current was not sensitive to Ni2+ , when it was activated downstream to the β-adrenoceptors using 10 μM forskolin (an adenylyl cyclase activator). When 10 μM forskolin was applied under NCX-selective recording conditions, the Ni2+ -sensitive current did not differ between control and forskolin. These findings suggest that in rabbit myocytes: (a) a PKA-activated Cl− current contributes to the Ni2+ -sensitive current activated via β-adrenoceptor stimulation under recording conditions previously considered selective for INCX ; (b) downstream activation of PKA does not augment Ni2+ -sensitive INCX , when this is measured under conditions where the Ni2+ -sensitive PKA-activated Cl− current is not present.