Structural biology of gap junctions and related hemichannels and their modulation by cellular factors

Large pore channels facilitate the exchange of biological material across intercellular channels that are referred to as gap junctions. Connexins are the conventional intercellular channels that mediate electrical neurotransmission across synapses and are modulated by several intracellular factors like calmodulin. On the other hand, other members of the family resemble the structural organisation of connexin hemichannels, but are primarily involved in the efflux of ATP from cells. The ATP-release channels are also called Pannexins and are vital to mediate apoptotic cell death and inflammation processes. The ATP release is mediated by the C-terminus of the Pannexin channels that control entry into the channel pore and cleavage of the C-terminus leads to large efflux of ATP from cells. Several inhibitors block Pannexin activity including carbenoxolone, probenecid and trovafloxacin and the proposal aims to study the binding sites of these inhibitors and ATP within pannexins.