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Structure-function relationship of the sodium channel rat brain IIA
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|Title:||Structure-function relationship of the sodium channel rat brain IIA|
|Abstract:||Sodium channels are voltage-gated transmembrane proteins propagating electrical signals in neurons, heart and skeletal muscle cells. Cloning and subsequent expression in heterologous systems has yielded structure-function information about wildtype and mutant Na channels. The protein's a. subunit has four homologous and highly conserved domains (I-IV), each consisting of six transmembrane segments. The fourth segment (54) of each domain carries evenly spaced and positively charged amino adds and has been proposed to function as voltage sensor. The patch clamp technique was used to investigate Na channel mutations that substitute or screen a IIS4 charge in excised membrane patches from Xenopus oocytes expressing channels encoded by wildtype rat brain TIA (RBIIA) or single-point mutation cDNAs (K859Q or L860F). Since Na channels were expressed from singular mRNA, they are presumed to represent a single, homogeneous population. However, the initial characterization of wildtype Na currents revealed an unexpected behavior: After excision of membrane patches from the cytosolic environment, there was a unidirectional and time-dependent transition in channel inactivation from slow to fast kinetics, paralleled by alterations in voltage dependence. This suggests that a single sodium Na channel can adopt at least two distinguishable gating modes, whose equilibrium may be modified by biochemical processes. Moreover, Na channel characteristics were affected by modification of the molecular structure in the point mutations K859Q and L860F. Both mutants induce similar shifts in the current-voltage relationship and L860F affects the valence of activation. In addition, steady-state inactivation curves and kinetic rates of activation and inactivation differ considerably. These results challenge the notion that 54 segments exclusively control the activation of Na channels. Rather, it seems that specific locations within the protein may affect multiple features of Na channel function.|
|Description:||Thesis (Ph. D.)--University of Hawaii at Manoa, 1993.|
vii 70 leaves, bound ill. 29 cm
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|Appears in Collections:||Ph.D. - Biomedical Sciences|
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