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Feliksas BukauskasProfessor Office: (718) 430-4130
Lab Webpage: connexons.aecom.yu.edu |
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De-novo formation, gating and regulation of gap junction channels and hemichannels.Our major goal is 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, intracellular pH, Ca 2+ concentration and metabolic communication 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 there are two distinct gating mechanisms in GJs, fast and slow/loop. A residual conductance is observed with the closure of the fast gate to a residual state, which serves as a selective filter that preserves electrical cell-cell signaling but restricts metabolic communication and chemical signaling. We propose that clustering of GJ channels into junctional plaques (JPs) is central to their ability to function. Currently, we are testing the hypothesis that JP formation starts with the aggregation of hemichannels into hemichannel plaques (HPs), followed by the superposition of HPs from apposing cells, docking of apposing hemichannels and channel pore opening. We reported that only ~1-15 % of GJ channels that assemble JPs are functional. We also examine conditions under which heterotypic junctions exhibit nearly unidirectional electrical signaling and may function as rectifying electrical synapses. Furthermore, we found that the flux (J j) of metabolites through Cx43/Cx45 GJs and other heterotypic junctions is affected by ionophoresis and transjunctional voltage (V j) and that the J j-V j dependence is asymmetric. The asymmetry is modulated by both differences in the resting potentials of the communicating cells and bursts of high frequency action potentials resembling those that occur during neuronal activity or tachyarrhythmia. This modulation of intercellular signalling can play a crucial role in many aspects of intercellular communication in excitable and non-excitable tissues. Finally, we study the role of Cxs in the development and spread of apoptosis and necrosis under normal and pathological conditions and the Cx mutants related to deafness, oculodentodigital dysplasia, cardiac arrhythmia and other hereditary diseases.
Selected Publications
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