Feliksas F. Bukauskas, Ph.D.

For more details, see the Website: http://connexons.aecom.yu.edu 

Our major goals are to study de-novo formation, gating and regulation of gap junction (GJ) channels and unapposed/nonjunctional hemichannels formed by connexin (Cx) proteins. GJ channels mediate direct cell-cell exchange of cytosolic ions and molecules. By combining electrophysiological, imaging and computational modeling methods, we examine electrical cell-cell coupling and metabolic communication under normal conditions and changes of intracellular pH, Ca, Mg and other reagents in living cells that express different types of wild type Cxs, their mutants and Cxs fused with color variants of green fluorescent protein (Cx-GFP). We demonstrated that in each hemichannel of the GJ channel there are two distinct types of gating mechanisms, fast and slow/loop, and that the fast gate can serve as a selective filter that preserves electrical cell-cell signaling but restricts metabolic communication and chemical signaling. We developed a stochastic multi-state model describing voltage-gating of homotypic and heterotypic GJ channels combined with methods of global coordinate optimization for automated characterization of fast and slow gates from experimental measurements of voltage gating. We propose that clustering of GJ channels into junctional plaques (JPs) is central to their ability to function. We reported that depending on Cx isoform, only ~0.003-0.15 of GJ channels clustered in JPs are functional and this fraction can be significantly modulated by pHi, Ca, Mg, arachidonic acid, long chain alkanols, albumin and other factors. Furthermore, we demonstrated that heterotypic junctions can exhibit nearly unidirectional electrical signaling and may function as rectifying electrical synapses and that the transjunctional flux of metabolites is affected by ionophoresis and voltage-sensitive gating, which can synergistically or antagonistically affect  metabolic communication. Furthermore, we study the role of Cxs in the spread of apoptosis and Cx mutants related to deafness, oculodentodigital dysplasia (ODDD), X-linked Charcot-Marie-Tooth disease, cardiac arrhythmia and other hereditary diseases.