Novel mutations in the KCNQ2 gene link epilepsy to a dysfunction of the KCNQ2-calmodulin interaction

• Published in: Journal of medical genetics Vol. 41; no. 3; pp. e35 - 35
• Main Authors: Richards, M C, Heron, S E, Spendlove, H E, Scheffer, I E, Grinton, B, Berkovic, S F, Mulley, J C, Davy, A
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.03.2004; BMJ Publishing Group LTD; BMJ Group
• Subjects: benign familial neonatal seizures; BFNS; C-terminus; calmodulin; Calmodulin - genetics; Calmodulin - metabolism; CaM; carboxy terminus; Cloning; DNA Mutational Analysis; Epilepsy; Epilepsy - genetics; Epilepsy - physiopathology; Female; first to sixth transmembrane domains; Genes; Genetic Testing; Homo sapiens potassium voltage gated channel; Humans; Infant, Newborn; Infant, Newborn, Diseases - genetics; KCNQ2; KCNQ2 Potassium Channel; KCNQ3; KQT-like subfamily; M-current; Male; member 2; member 3; Mutation; Mutation - genetics; neuronal muscarinic regulated current; Online Mutation Report; P-loop; Pedigree; pore loop; potassium channel; Potassium Channels - chemistry; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels, Voltage-Gated; Protein Binding; Proteins; Rodents; S1–6; Seizures - genetics; Structure-Activity Relationship; Two-Hybrid System Techniques; Yeast
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2003.013938

The M-current is a slowly activating, non-inactivating potassium conductance known to regulate neuronal excitability by determining the firing properties of neurones and their responsiveness to synaptic input. 11 Because it is active at voltages near the threshold for action potential initiation, the M-current has a major impact on neuronal excitability. Since the KCNQ2/KCNQ3 ion channel plays a pivotal role in the regulation of neuronal excitability, it is not surprising that several mutations in the gene have been associated with epilepsy. In the case of the KCNQ2 L619R mutation that results in increased binding of CaM to the M-channel, it can be inferred that the effect of bradykinin modulation of M-channels would be amplified because of a likely increased sensitivity to [Ca2+]. [...]in the case of the L619R mutant channel, in response to a rise in bradykinin-induced intracellular [Ca2+], the KCNQ2/KCNQ3 derived M-current would be suppressed to a greater extent than for the wild-type channel.