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KCTD12

Official Full Name
potassium channel tetramerization domain containing 12
Synonyms
PFET1; PFETIN; C13orf2

Recent Research

Potassium channel tetramerization domain containing 12 (KCTD12), also known as Pfetin, is a member of the KCTD family which consists of 26 members. KCTD12 contains a voltage-gated potassium (K+) channel tetramerization T1 domain and a BTB/POZ (Bric-a-brac, Tram-track, Broad complex poxvirus and zinc finger) domain. KCTD12 was firstly identified in cochlea. In addition to being a K+ channel protein that responds to membrane potential, KCTD12 also acts as an auxiliary subunit of GABAB (γ-aminobutyric acid type B) receptors, which regulate emotionality and neuronal excitability.

In the adult mouse brain, KCTD12 is expressed highly in amygdala and hippocampus, with the KCTD12 protein localized primarily postsynaptically. GABA is a major inhibitory neurotransmitter in the central nervous system of mammals acting on ionotropic GABAA and metabotropic GABAB receptors. KCTD12 stabilizes GABAB receptors at the cell surface and regulates kinetic properties of the receptor response. Its coding protein KCTD12 has been reported to induce GABAB receptor-activated K+ current desensitization by binding to the βγ subunits of the activated G-protein, which interferes with activation of the effector K+ channel. Besides, the post-receptor mechanism of desensitization is receptor specific through the exclusive binding of natural KCTD12 protein to GABAB receptor. More importantly, KCTD12 overexpression and the correlation between KCTD12 overexpression and higher tumor grades have been reported in studies regarding gastrointestinal stromal tumors. And KCTD12 has been shown to function as a tumor suppressor in studies regarding colon cancer.

In addition, KCTD12 gene negatively regulates habenular dendritogenesis. The expression of KCTD12 is conserved throughout the vertebrate lineage. In zebrafish, there are two homologous genes with different expression patterns in the subnucleus of habenula. KCTD12.1 is expressed in the lateral subnuclei but KCTD12.2 is expressed in the medial subnuclei. KCTD12 proteins are found in the cytoplasm of habenular neurons, including within the dendrites. During dendritogenesis, KCTD12 regulates the activity of Ulk2, a serine/threonine kinase that promotes filopodial extension during neuronal process formation. Ulk2 is expressed throughout both habenular subnuclei, beginning at 48 hours post fertilization (hpf) until at least 96 hpf. Previous work has shown that KCTD12.1 interacts with Ulk2. The presence of KCTD12 appears to inhibit Ulk2 activity, and as a result, dendritogenesis is reduced.

At last, it has been demonstrated that KCTD12 is down-regulated in the cancer stem-like cells of colorectal cancer (CRC). The silencing of endogenous KCTD12 and the overexpression of ectopic KCTD12 dramatically enhances and represses CRC cell stemness, respectively, as assessed in vitro and in vivo using a colony formation assay, a spheroid formation assay and a xenograft tumor model.

References:

  1. Cathomas F, et al. Altered emotionality and neuronal excitability in mice lacking KCTD12, an auxiliary subunit of GABAB receptors associated with mood disorders. Translational Psychiatry, 2015, 5(2):e510.
  2. Adelfinger L, et al. GABAB receptor phosphorylation regulates KCTD12-induced K+ current desensitization. Biochemical Pharmacology, 2014, 91(3):369-379.
  3. Stacey L, et al. Kctd12 and Ulk2 Partner to Regulate Dendritogenesis and Behavior in the Habenular Nuclei. PLoS ONE, 2014, 9(10):e110280-.
  4. Li L, et al. KCTD12 Regulates Colorectal Cancer Cell Stemness through the ERK Pathway. Sci Rep, 2016, 6:20460.

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