Two pores instead of one: Gating pore current and the electrical leak in autism and epilepsy

Imagine the brain as a dynamic city, where countless vehicles traverse major arterial roads and branching side streets. The smooth traffic flow depends on a balance between excitatory neurons, which act as main roads encouraging vehicles to move forward, and inhibitory neurons, represented by branching side streets that regulate and control the traffic flow back onto the main route. Both systems work in tandem to maintain efficient operations, preventing gridlock or chaos. Zooming in further, the voltage-gated ion channels within neurons resemble traffic lights on arterial roads or side streets. Green means go, red means stop, and yellow signals caution. These channels regulate the flow of bioelectric signals, coordinating transitions between green, yellow, and red-analogous to an action potential. In excitatory neurons (major roads), voltage-gated sodium channels act as green lights, allowing sodium ions to flow in during depolarization. In contrast, voltage-gated potassium channels serve as yellow lights, eventually signaling red to terminate the action potential. In inhibitory neurons (side streets), sodium influx produces action potentials that ultimately control and limit traffic on the major roads. This analogy can be extended to describe neuropsychiatric and neurological disorders, such as autism spectrum disorder (ASD) and epilepsy, which arise from mutations in voltage-gated ion channels. These mutations alter the channels' ability to open and close properly, disrupting the timing and duration of red, yellow and green signals and impairing traffic flow. Now, picture yourself on a major arterial road with green and red flickering simultaneously. Such a disastrous scenario could lead to even more dangerous outcomes, with cars moving when they should stop or stopping when they should move. This specific analogy illustrates a key feature of certain mutations in voltage-gated ion channels that result in the gating pore current (I_gp), a secondary pore that leaks electrical current. This mini-review focuses on I_gp caused by mutations in the gating charge residues of voltage-gated ion channels. We will discuss how I_gp contributes to the pathophysiology of ASD and epilepsy and explore therapeutic strategies targeting this mechanism.