2.B.54. The Small Molecule Uncoupling Protonophore (SMUP) Superfamily 

Excessive build-up of mitochondrial protonic potential is harmful to cellular homeostasis, and modulation of inner membrane permeability provides a means to counteract this build-up. countermeasure. Holmuhamedov et al. 2004 demonstrated that structurally distinct potassium channel openers, diazoxide and pinacidil, facilitate transmembrane proton translocation, generating H+-selective current through planar phospholipid membranes. Both openers depolarized mitochondria, activated state 4 respiration and reduced oxidative phosphorylation, recapitulating the signature of mitochondrial uncoupling. This effect was maintained under K+-free conditions and shared the characteristics of the prototypic protonophore 2,4-dinitrophenol. Diazoxide, pinacidil and 2,4-dinitrophenol, but not 2,4-dinitrotoluene, lacking protonophoric properties, preserved functional recovery of the ischemic heart. The identified protonophoric property of potassium channel openers suggests a previously unrecognized component in their mechanism of cardioprotection (Holmuhamedov et al. 2004).



Holmuhamedov, E.L., A. Jahangir, A. Oberlin, A. Komarov, M. Colombini, and A. Terzic. (2004). Potassium channel openers are uncoupling protonophores: implication in cardioprotection. FEBS Lett. 568: 167-170.