Participation of PKG and PKA-related pathways in the IFN-γ induced modulation of the BK channel activity in human cardiac fibroblasts.

This study was devoted to elucidating the interferon (IFN)-γ-induced signaling pathway and the interaction between protein kinase G (PKG) and protein kinase A (PKA) through large-conductance Ca(2+)-activated K(+) channels in human cardiac fibroblasts. The I currents were recorded using a whole-cell patch clamp method. A large depolarization (+50 mV) and a high Ca concentration (pCa 6.0) were used in the internal pipette solution to activate only the K channels. Iberiotoxin (Ibtx), which selectively inhibits BK channels at a concentration of 100 nmol/l, caused a significant reduction of basal I. Adding IFN-γ in the presence of Ibtx had no effect on I. Application of the IFN-γ caused a significant reduction in total K current amplitude, recorded with a 500 ms depolarizing pulse duration, to +50 mV from a holding potential of -80 mV. We tested the involvement of the sGC/cGMP/PKG signaling pathway by using specific PKG inhibitor KT 5823, potent sGC inhibitor NS 2028, and specific sGC agonist BAY 41-8543. The obtained data confirmed that only sGC participated in the IFN-γ-mediated BK channel modulation, which was mediated further by PKA. This study represents first evidence about the participation of the IFN-γ in the mechanisms responsible for BK modulation in HCFs. We also believe that this process occurs via negative crosstalk between the PKG- and PKA-associated pathways.