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Updated: Aug 11, 2026
Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes
Published on: March 12, 2013
A spontaneous mutation involving Kcnq2 (Kv7.2) reduces M-current density and spike frequency adaptation in mouse CA1
James F Otto1, Yan Yang, Wayne N Frankel
1Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, USA.
Abstract:
The M-type K+ current [IK(M)] activates in response to membrane depolarization and regulates neuronal excitability. Mutations in two subunits (KCNQ2 and KCNQ3; Kv7.2 and Kv7.3) that underlie the M-channel cause the human seizure disorder benign familial neonatal convulsions (BFNC), presumably by reducing IK(M) function. In mice, the Szt1 mutation, which deletes the genomic DNA encoding the KCNQ2 C terminus and all of CHRNA4 (nicotinic acetylcholine receptor alpha4 subunit) and ARFGAP-1 (GTPase-activating protein that inactivates ADP-ribosylation factor 1), reduces seizure threshold, and alters M-channel pharmacosensitivity. Genomic deletions affecting the C terminus of KCNQ2 have been identified in human families with BFNC, and truncation of the C terminus prevents proper KCNQ2/KCNQ3 channel assembly in Xenopus oocytes. We showed previously that Szt1 mice have a reduced baseline seizure threshold and altered sensitivity to drugs that act at the M-channel. Specifically, the proconvulsant M-channel blocker linopirdine and anticonvulsant enhancer retigabine display increased and decreased potency, respectively, in Szt1 mice. To investigate the effects of the Szt1 mutation on IK(M) function explicitly, perforated-patch electrophysiology was performed in CA1 pyramidal neurons of the hippocampus in brain slices prepared from C57BL/6J-Szt1/+ and control C57BL/6J+/+ mice. Our results show that Szt1 reduces both IK(M) amplitude and current density, inhibits spike frequency adaptation, and alters many aspects of M-channel pharmacology. This is the first evidence that a naturally occurring Kcnq2 mutation diminishes the amplitude and function of the native neuronal IK(M), resulting in significantly increased neuronal excitability. Finally, the changes in single-cell biophysical properties likely underlie the altered seizure threshold and pharmacosensitivity reported previously in Szt1 mice.
Insights
The Szt1 mutation in KCNQ2 reduces M-type potassium current (IK(M)) amplitude and function, increasing neuronal excitability and altering drug sensitivity in mice.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The M-type K+ current (IK(M)) is crucial for regulating neuronal excitability.
- Mutations in KCNQ2 and KCNQ3 subunits cause benign familial neonatal convulsions (BFNC).
- The Szt1 mutation in mice affects KCNQ2, CHRNA4, and ARFGAP-1, impacting seizure threshold and M-channel drug sensitivity.
Purpose of the Study:
- To investigate the explicit effects of the Szt1 mutation on native neuronal IK(M) function.
- To determine how the Szt1 mutation impacts M-channel biophysical properties and neuronal excitability.
Main Methods:
- Perforated-patch electrophysiology was performed on hippocampal CA1 pyramidal neurons from Szt1 mutant and control mice.
- Brain slices from C57BL/6J-Szt1/+ and C57BL/6J+/+ mice were used for electrophysiological recordings.
Main Results:
- The Szt1 mutation significantly reduced IK(M) amplitude and current density.
- Spike frequency adaptation was inhibited in neurons with the Szt1 mutation.
- M-channel pharmacology was altered, with changes in drug potency observed.
Conclusions:
- This study provides the first evidence that a naturally occurring Kcnq2 mutation diminishes native neuronal IK(M) amplitude and function.
- The observed reduction in IK(M) leads to increased neuronal excitability.
- Altered single-cell biophysical properties likely explain the previously reported changes in seizure threshold and pharmacosensitivity in Szt1 mice.
