Autism-associated mutations in K_V7 channels induce gating pore current.

Area of Science:

• Neuroscience
• Genetics
• Ion Channel Physiology

Background:

• Autism spectrum disorder (ASD) affects over 1% of US children, causing social, behavioral, and communication deficits.
• Genome sequencing has identified over 500 genes implicated in ASD, including mutations in voltage-gated potassium (K_V7) channels.
• Specific mutations altering arginine gating charges in K_V7 channels are frequently associated with ASD.

Purpose of the Study:

• To investigate the functional consequences of gating charge mutations in K_V7 channels.
• To determine if these mutations induce gating pore current (ionic leak) in the voltage sensor.
• To explore the role of gating pore current in the pathophysiology of ASD.

Main Methods:

• Electrophysiological recordings of wild-type and mutant K_V7 channels (bacterial and human).
• Analysis of gating pore current under various membrane potentials.
• In vivo expression of a specific ASD-associated K_V7 mutation (K_V7.3/R2C) in mouse midbrain dopamine neurons.

Main Results:

• Wild-type K_V7 channels exhibit outward gating pore current at positive potentials due to a native glutamine.
• ASD-associated mutations at R1/R2 positions induce inward gating pore current at negative potentials.
• Mutation at R4 position causes outward gating pore current at positive potentials.
• In vivo expression of K_V7.3/R2C disrupts action potential generation and repetitive firing in mouse dopamine neurons.

Conclusions:

• Gating pore current is a native property of K_V7 channels and is altered by ASD-associated mutations.
• Mutant K_V7 channels can conduct significant ionic current through their voltage sensors.
• Altered action potential generation due to gating pore current in mutant K_V7 channels is a potential pathogenic mechanism in autism.