Reduced density and altered regulation of rat atrial L-type Ca²⁺ current in heart failure

Constitutive regulation by PKA has recently been shown to contribute to L-type Ca²⁺ current (I_CaL) at the ventricular t-tubule in heart failure. Conversely, reduction in constitutive regulation by PKA has been proposed to underlie the downregulation of atrial I_CaL in heart failure. The hypothesis that downregulation of atrial I_CaL in heart failure involves reduced channel phosphorylation was examined. Anesthetized adult male Wistar rats underwent surgical coronary artery ligation (CAL, N=10) or equivalent sham-operation (Sham, N=12). Left atrial myocytes were isolated ~18 wk postsurgery and whole cell currents recorded (holding potential=-80 mV). I_CaL activated by depolarizing pulses to voltages from -40 to +50 mV were normalized to cell capacitance and current density-voltage relations plotted. CAL cell capacitances were ~1.67-fold greater than Sham (P ≤ 0.0001). Maximal I_CaL conductance (G_max ) was downregulated more than 2-fold in CAL vs. Sham myocytes (P < 0.0001). Norepinephrine (1 micromol/l) increased G_max >50% more effectively in CAL than in Sham so that differences in I_CaL density were abolished. Differences between CAL and Sham G_max were not abolished by calyculin A (100 nmol/l), suggesting that increased protein dephosphorylation did not account for I_CaL downregulation. Treatment with either H-89 (10 micromol/l) or AIP (5 micromol/l) had no effect on basal currents in Sham or CAL myocytes, indicating that, in contrast to ventricular myocytes, neither PKA nor CaMKII regulated basal I_CaL Expression of the L-type α_1C-subunit, protein phosphatases 1 and 2A, and inhibitor-1 proteins was unchanged. In conclusion, reduction in PKA-dependent regulation did not contribute to downregulation of atrial I_CaL in heart failure.NEW & NOTEWORTHY Whole cell recording of L-type Ca²⁺ currents in atrial myocytes from rat hearts subjected to coronary artery ligation compared with those from sham-operated controls reveals marked reduction in current density in heart failure without change in channel subunit expression and associated with altered phosphorylation independent of protein kinase A.