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 α-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 α- and β₁-subunits) was reduced in cells cultured on the stiff substrate. Furthermore, in HEK293 cells coexpressing the cardiac Ca_V1.2 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_V1.2 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.