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KCNQ2 : Molecular relation to benign familial neonatal convulsion (BFNC). Calvin Leung, Daniel Nixon, Kristian Adams & Josefine Pedersen . Today…. Topography M Current Benign Familial Neonatal Convulsion (BFNC) Mutation – R214W. KCNQ2. Chromosome 20q13.3
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KCNQ2: Molecular relation to benign familial neonatal convulsion (BFNC) Calvin Leung, Daniel Nixon, Kristian Adams& JosefinePedersen
Today… • Topography • M Current • Benign Familial Neonatal Convulsion (BFNC) • Mutation – R214W
KCNQ2 • Chromosome 20q13.3 • Base pair 62,037,541 to base pair 62,103,992 • Codes for Kv7.2 - – Potassium voltage gated • 872 amino acids in length
Kv7.2 Topography
Dynamics of K+ Movement Source: Khalili-Araghi, Tajkhorshid & Schulten, 2006
R214W Mutations of KCNQ2
Topography of the Kv7.2 subunit (Cooper and Jan, 2003)
R214W Current traces from Xenopus oocytes expressing homomeric channels in response to a family of voltage steps from -80 to +40 mV in 10 mV increments. Scale - 200 nA, 500 ms. Current traces from heteromeric channels expressed in Xenopus oocytes in response to a family of voltage steps from -80 to +40 mV in 10 mV increments. Scale - 100 nA, 500 msec. (Castaldo et al, 2002)
Activation/Deactivation Kinetics (Castaldo et al, 2002)
Changes in Voltage Dependence Voltage dependence of conductance of homomeric (left) and heteromeric (right) M-Channels. (Castaldo et al, 2002)
Maximal Current of Normal/Mutants (Castaldo et al, 2002)
Summary – R214W • Substitution of the positive arginine residue (R214) with tryptophan (W) in the voltage-sensing S4 domain. • Both homomeric and heteromeric mutant channels exhibit delayed activation, accelerated deactivation, and decreased voltage sensitivity in response to depolarising stimuli. • However, the maximal current and surface expression remain unchanged, unlike other mutations that occur at the pore loop or at the C-terminus of KCNQ2. • Therefore, the M-current becomes more difficult to invoke in neurons that express these mutant channels. • As a result, neuronal excitability increases, leading to the development of BFNC.