Mitochondrial Ion Channels and Cardioprotection

Mitochondrial ATP-sensitive K(+) (mitoK(ATP)) and Ca(2+)-activated K' (mitoK(Ca)) channels exist in cardiac myocytes, and they play key roles in cardioprotection. We have recently reported that K' influx through mitoKATp or mitoKc channels occurs independently of each other and confers cardioprotection in a similar manner. Activation of mitoK(ATP) channel is augmented by protein kinase C (PKC), whereas mitoK(Ca) channel is activated by protein kinase A (PKA). However, phosphatidylinositol 3-kinase (PI3-K) is linked to neither mitoK(ATP) nor mitoK(Ca) channels. We have demonstrated that bioactive substances modulate the opening of mitoK(ATP) channels via a PKC-dependent pathway or opening of mitoK(Ca) channels via a PKA-dependent pathway and thereby protecting the heart from ischemia/reperfusion injury. Several endogenous substances such as adenosine and bradykinin can reduce infarct size by activation of mitoK(ATP) channels in a PKC-dependent manner. Adrenomedullin, a potent vasodilator peptide, potentiates the opening of mitoK(Ca) channels by PKA activation. Treatment with adrenomedullin prior to ischemia results in the reduction of infarct size via a PKA-mediated activation of mitoK(Ca) channels. Thus, some endogenous substances confer cardioprotection via PKA- or PKC-mediated activation of mitoK(ATP) or mitoK(Ca) channels.