Target Name: KCNK5
NCBI ID: G8645
Other Name(s): TWIK-related acid-sensitive K+ channel 2 | potassium channel, subfamily K, member 1 (TASK-2) | K2P5.1 potassium channel | potassium channel, subfamily, member 5 (KCNK5) | TWIK-related acid-sensitive K+ 2 | potassium channel, two pore domain subfamily K, member 5 | Potassium channel, subfamily K, member 1 (TASK-2) | KCNK5_HUMAN | TWIK-related acid-sensitive K(+) channel 2 | acid-sensitive potassium channel protein TASK-2 | KCNK5b | Acid-sensitive potassium channel protein TASK-2 | Potassium channel subfamily K member 5 | TASK-2 | potassium two pore domain channel subfamily K member 5 | K2p5.1 | TASK2 | Potassium two pore domain channel subfamily K member 5 | FLJ11035

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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KCNK6 | KCNK7 | KCNK9 | KCNMA1 | KCNMB1 | KCNMB2 | KCNMB2-AS1 | KCNMB3 | KCNMB4 | KCNN1 | KCNN2 | KCNN3 | KCNN4 | KCNQ Channels (K(v) 7) | KCNQ1 | KCNQ1DN | KCNQ1OT1 | KCNQ2 | KCNQ3 | KCNQ4 | KCNQ5 | KCNQ5-AS1 | KCNQ5-IT1 | KCNRG | KCNS1 | KCNS2 | KCNS3 | KCNT1 | KCNT2 | KCNU1 | KCNV1 | KCNV2 | KCP | KCTD1 | KCTD10 | KCTD11 | KCTD12 | KCTD13 | KCTD13-DT | KCTD14 | KCTD15 | KCTD16 | KCTD17 | KCTD18 | KCTD19 | KCTD2 | KCTD20 | KCTD21 | KCTD21-AS1 | KCTD3 | KCTD4 | KCTD5 | KCTD5P1 | KCTD6 | KCTD7 | KCTD8 | KCTD9 | KDELR1 | KDELR2 | KDELR3 | KDF1 | KDM1A | KDM1B | KDM2A | KDM2B | KDM3A | KDM3B | KDM4A | KDM4B | KDM4C | KDM4D | KDM4E | KDM5A | KDM5A-GATAD1-EMSY chromatin complex | KDM5B | KDM5C | KDM5D | KDM6A | KDM6B | KDM7A | KDM7A-DT | KDM8 | KDR | KDSR | KEAP1 | Kelch-like protein | KERA | Keratin | KHDC1 | KHDC1L | KHDC1P1 | KHDC3L | KHDC4 | KHDRBS1 | KHDRBS2 | KHDRBS3 | KHK | KHNYN | KHSRP | KHSRPP1