KCNQ2 : Molecular relation to benign familial neonatal convulsion (BFNC)

1. KCNQ2: Molecular relation to benign familial neonatal convulsion (BFNC) Calvin Leung, Daniel Nixon, Kristian Adams& JosefinePedersen

2. Today… • Topography • M Current • Benign Familial Neonatal Convulsion (BFNC) • Mutation – R214W

3. 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

4. Kv7.2 Topography

5. Kv7.2

6. Dynamics of K+ Movement Source: Khalili-Araghi, Tajkhorshid & Schulten, 2006

7. R214W Mutations of KCNQ2

8. Topography of the Kv7.2 subunit (Cooper and Jan, 2003)

9. R214W

10. 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)

11. Activation/Deactivation Kinetics (Castaldo et al, 2002)

12. Changes in Voltage Dependence Voltage dependence of conductance of homomeric (left) and heteromeric (right) M-Channels. (Castaldo et al, 2002)

13. Maximal Current of Normal/Mutants (Castaldo et al, 2002)

14. Surface Expression of Normal/Mutant

15. 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.