Molecular domains determining gap junction channel properties

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Gap junction channels are specialized membrane pore structures between neighbouring cells, allowing ions and small molecules in one cell to pass on to the neighbour cells. The building blocks for gap junction channels are a group of transmembrane proteins called connexins (Cx). There are 20 different types of connexins are identified in rodents. Six identical connexins or different connexins form a cylinder-shaped half gap junction channel known as hemichannel. End-to-end docking of two hemichannels forms a complete gap junction channel. Communications through gap junction channels are essential for synchronized and coordinated cellular activities in tissues and organs. The gap junction channel pore size, the switch control for opening/closing, and the modulations by chemicals are different depending on the channel component connexin subtypes. This proposal aims to reveal which part of the connexin molecule is responsible for the distinct channel functional properties of the neuronal connexin, Cx36, and the eye lens connexin, Cx50. We plan to switch the key pore-lining domains from Cx36 into Cx50 or vise versa to generate Cx50 or Cx36 chimeras. These chimera proteins will be expressed into gap junction-deficient cells for functional test of gap junction channel properties. Further subdivision of positively identified domain will be used to track down the minimum amino acid residue(s) required to display unique functional properties. The proposed research will assist us in understanding the molecular mechanisms in the control of opening/closing of these important channels and the molecular determinants for the ability of the channel to conduct ions. A comprehensive knowledge of structure-function relationships for gap junction channels in neurons and in the lens is critical in the understanding of the physiological functions of these important intercellular channels.