(13) A CURRENT WORKING MODEL FOR THE STRUCTURAL CHANGES THAT OCCUR DURING VOLTAGE GATING IN VDAC

Marco Colombini (1), Jinming Song (1), Elizabeth Blachly-Dyson (2) and Michael Forte (2)
(1) Dept. of Biology, University of Maryland, College Park, MD 20742
(2)Vollum Inst., Oregon Health Science Univ., Portland, OR 97201

The mitochondrial channels called VDAC (or loosely referred to as mitochondrial porin) exist in multiple isoforms in many species. In all tested species, at least one isoform (usually referred to as VDAC1) has the canonical electrophysiological properties attributed to VDAC: a conductance of 4 nS in 1M KCl, 2:1 selectivity for Cl- over K+ in 1M vs 0.1 M KCl; and voltage-dependent closure at both positive and negative potentials to a family of low-conducting states of reduced or inverted selectivity. Existing evidence from a variety of experimental approaches places severe constraints on the possible structure and gating mechanism of these canonical VDAC channels. The transmembrane strands have been identified by means of selectivity and topology experiments. The voltage-sensor domains, responsible for voltage gating and for changing the selectivity of the channel, were identified by 3 independent experiments: 1) state-dependent selectivity changes, 2) state-dependent surface accessibility, and 3) discrete changes in the steepness of the voltage dependence. The extent of physical motion indicated by the surface-accessibility experiments can be reconciled with the results of experiments assessing the electrical distance moved. The gating mechanism proposed must also be consistent with the measured effective pore diameters in the open and closed states, the pore volume change, the kinetics of the 2 gating processes and the enthalpy and entropy changes associated with these processes. The experimental evidence will be summarized and a working model will be presented that is consistent with this evidence.