KCNK5 as a Potential Drug Target: A Review of TWIK-Related Acid-Sensitive K+ Channels

Target Name: KCNK5

NCBI ID: G8645

KCNK5 as a Potential Drug Target: A Review of TWIK-Related Acid-Sensitive K+ Channels

Abstract:

KCNK5, a member of theIKAP family, is a K+ channel that plays a crucial role in the regulation of neural excitability and muscle contractions. TheTWIK-related acid-sensitive K+ channels (TWIK-ASKs) are a subfamily ofKCNK5 that have unique properties due to the presence of an acid-sensing loop. This article aims to review the current research on TWIK-ASKs, including their structure, function, and potential as drug targets.

Introduction:

KCNK5 is a family ofK+ channels that are involved in the regulation of neural and muscle excitability. TheKCNK5 gene has four splice variants, each generating a different isoform. The most abundant is the full-length gene (IKAPK2), which encodes the N-terminus of the channel. The other isoforms are N-linked, middle-length, and C-linked, which result from the exclusion of exon 11 and exon 12, respectively (1,2).

The TWIK-ASKs are a subfamily ofKCNK5 that have unique properties due to the presence of an acid-sensing loop. These channels are characterized by the presence of two distinct acid-sensing regions, one located at the N-terminus of the channel and the other at the C-terminus (3,4). The acid-sensing loop is a short loop of amino acids that contains two positively charged residues (ASP-2 and Asp-3) and is responsible for the sensitivity of the channel to acidic and basic conditions (5,6).

Structure and Function:

The TWIK-ASKs share a common framework with otherKCNK5 isoforms, with a K+ channel that consists of an N-terminus, a body, and a C-terminus (7,8). However, the TWIK-ASKs differ from otherKCNK5 isoforms due to their unique acid-sensing loop. This loop is composed of three amino acids: Asp-2, Asp-3, and Glu-3 (9,10).

The acid-sensing loop plays a crucial role in the regulation of the channel's conductivity. The presence of the acid-sensing loop allows the channel to remain closed in the presence of basic conditions, such as high levels of intracellular potassium ions (K+ ions) (11,12). In contrast, the acid-sensing loop allows the channel to remain open in the presence of acidic conditions, such as low levels of K+ ions (13,14).

In addition to its role in channel regulation, the acid-sensing loop is also involved in the regulation of other cellular processes. For example, the acid-sensing loop has been shown to play a role in the regulation of neurotransmitter release (15,16) and in the modulation of cellular signaling pathways (17,18).

Potential as Drug Targets:

The TWIK-ASKs have great potential as drug targets due to their unique properties and their involvement in various cellular processes. Several studies have shown that inhibitors of the TWIK-ASKs can have therapeutic effects in various neurological and psychiatric disorders, including epilepsy, schizophrenia, and Alzheimer's disease (19,20).

For example, several studies have shown that inhibitors of the TWIK-ASKs can be effective in treating epilepsy, a disorder characterized by the recurrent and sometimes severe episodes of electrical activity (21,22). The TWIK-ASKs are involved in the regulation of neural excitability, and therefore, their inhibition can lead to a reduction in the number of epileptic episodes (23,24).

Another example is the treatment of

Protein Name: Potassium Two Pore Domain Channel Subfamily K Member 5

Functions: pH-dependent, outwardly rectifying potassium channel (PubMed:9812978). Outward rectification is lost at high external K(+) concentrations (PubMed:9812978)

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