A Role of BK Channel in Regulation of Ca2+ Channel in Ventricular Myocytes by Substrate Stiffness

Substrate stiffness is crucial for diverse cell functions, but the mechanisms conferring cells with mechanosensitivity are still elusive. By tailoring substrate stiffness with 10-fold difference, we showed that L-type voltage-gated Ca2+ channel current density was greater in chick ventricular myocytes cultured on the stiff substrate than on the soft substrate. Blockage of the BK channel increased the Ca2+ current density on the soft substrate and consequently eliminated substrate stiffness regulation of the Ca2+ channel. The expression of the BK channel, including the STREX-containing alpha-subunit that forms stretch-activated BK channel in myocytes and the BK channel function in myocytes (and also in HEK293 cells heterologously expressing STREX-containing alpha-and beta(1)-subunits) was reduced in cells cultured on the stiff substrate. Furthermore, in HEK293 cells coexpressing the cardiac Ca(V)1.2 channel and STREX-containing BK channel, the Ca2+ current density was greater in cells on the stiff substrate, which was not observed in cells expressing the Ca(V)1.2 channel alone or coexpressing with the STREX-deleted BK channel. These results provide strong evidence to show that the stretch-activated BK channel plays a key role in functional regulation of cardiac voltage-gated Ca2+ channel by substrate stiffness, revealing, to our knowledge, a novel mechanosensing mechanism in ventricular myocytes.