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Publication - Professor Neil Marrion

    Small conductance calcium-activated potassium channels: from structure to function


    Weatherall, K, Goodchild, S, Jane, D & Marrion, N, 2010, ‘Small conductance calcium-activated potassium channels: from structure to function’. Progress in Neurobiology, vol 91., pp. 242 - 255


    The cloning of KCa2 channels revealed three subtypes, with each displaying distinct but partially overlapping expression distributions in the mammalian CNS and periphery. Activation of KCa2 channels leads to membrane hyperpolarization and inhibition of action potential firing. Block of KCa2 channels has been suggested as a novel target for cognitive enhancement, depression, myotonic muscular dystrophy and heart arrhythmias. It is clear however, that blockers selective for individual KCa2 channel subtypes would be required to be therapeutically useful. KCa2 channel current is blocked by apamin, with the bee venom toxin being unusual in displaying some selectivity between KCa2 channel subtypes. This suboptimal selectivity is not sufficient to be therapeutically useful and the toxin has been shown in vivo to have a very narrow therapeutic window. Mutational and molecular modelling studies of the KCa2 channels are beginning to determine how selective block might be achieved. Mutagenesis has indicated the importance of the outer pore region and the extracellular loop between transmembrane domains S3 and S4 for block of KCa2 current by apamin. Mapping the sequence of transmembrane domains S5, pore helix and S6 onto the crystal structures of KcsA, MthK and Kv1.2 has provided an approximation of the pore structure. This approach has allowed structural modelling of the interactions between toxins and channel, demonstrating that the toxins that show little discrimination between KCa2 channel subtypes interact with the outer pore and around the K+ selectivity filter. We present the structural modelling of the interaction of apamin and KCa2.2, which is superimposed onto the crystal structure of Kv1.2. This has shown that apamin interacts only with the outer pore and does not come into contact with channel's selectivity filter. It is clear that by comparing how different toxins interact with each KCa2 channel subtype, a detailed picture will be generated that will aid the development of more specific KCa2 channel blockers.

    Full details in the University publications repository