Disease relevance of KCNQ4

• Whereas mutations in KCNQ1 cause deafness by affecting endolymph secretion, the mechanism leading to KCNQ4-related hearing loss is intrinsic to outer hair cells [1].
• The deafness-associated Jervell and Lange- Nielsen syndrome (JLNS) mutation KCNE1(D76N) impairs KCNQ4-function whereas the Romano-Ward syndrome (RWS) mutant KCNE1(S74L), which shows normal hearing in patients, does not impair KCNQ4 channel function [2].
• Cells of the human neuroblastoma line SH-SY5Y were co-transfected transiently with KCNQ4 and D(2L) receptors [3].
• Differential expression of KCNQ4 in inner hair cells and sensory neurons is the basis of progressive high-frequency hearing loss [4].
• OBJECTIVE: To study nonsyndromic progressive sensorineural hearing loss (SNHL) with significant linkage to the DFNA2 locus on chromosome 1p in a Dutch kindred [5].

High impact information on KCNQ4

• KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness [1].
• It also suppresses the currents of KCNQ4 and HERG potassium channels [6].
• KCNQ4 mutations underlie human DFNA2 dominant progressive hearing loss [7].
• KCNQ4 is an M-type K+ channel expressed in sensory hair cells of the inner ear and in the central auditory pathway [7].
• Although KCNQ4 is strongly expressed in vestibular hair cells, vestibular function appeared normal [7].

Biological context of KCNQ4

• KCNQ4 was mapped to chromosome 1p34 and a single mutation was found in three patients from a small French family with non-syndromic autosomal dominant hearing loss [8].
• KCNQ4 is expressed in inner and outer hair cells of the inner ear where it influences electrical excitability and cell survival [2].
• The KCNQ4-expressing cells exhibited average resting membrane potentials of -56 mV in contrast to -12 mV recorded in the nontransfected cells [9].
• Using CHO cells as a mammalian expression system, we have examined the properties of KCNQ4 channels under different phosphorylation conditions [10].
• Here we describe two additional families originating from Europe and Japan with a KCNQ4 missense mutation (W276S) that was previously found in one European family [11].

Anatomical context of KCNQ4

• The KCNQ4 gene is thought to encode the molecular correlate of the I(K,n) in outer hair cells of the cochlea and I(K,L) in Type I hair cells of the vestibular apparatus, mutations in which lead to a form of inherited deafness [12].
• In conclusion, KCNEs are presumably coexpressed with KCNQ4 in hair cells from the organ of Corti and might regulate KCNQ4 functional properties, effects that could be important under physiological and pathophysiological conditions [2].
• Functional coassembly of KCNQ4 with KCNE-beta- subunits in Xenopus oocytes [2].
• The strongest expression of KCNQ4 in IHCc was in the base of the cochlea and in the apex for OHCs [13].
• Two hearing loss genes have been identified at this site: GJB3, the gene that encodes the gap junction protein connexin 31, and KCNQ4, a voltage-gated potassium channel gene [14].

Associations of KCNQ4 with chemical compounds

• We found that CaM overexpression reduced NEM augmentation of KCNQ2, KCNQ4, and KCNQ5, and NEM pretreatment reduced Ca2+/CaM-mediated suppression of M current in sympathetic neurons by bradykinin [15].
• To further localize the site of NEM action, we mutated three cysteine residues in the C terminus of KCNQ4 [16].
• KCNQ4 channel activation by BMS-204352 and retigabine [17].
• The KCNQ4 channels were blocked in a voltage-independent manner by the memory-enhancing M current blockers XE-991 and linopirdine with IC(50) values of 5.5 and 14 microM, respectively [9].
• The antiarrhythmic KCNQ1 channel blocker bepridil inhibited KCNQ4 with an IC(50) value of 9.4 microM, whereas clofilium was without significant effect at 100 microM [9].

Physical interactions of KCNQ4

• This might suggest modulation of KCNQ4 by interacting KCNE Beta-subunits, which are known to modify the properties of the closely related KCNQ1 [2].
• We suggest that KCNQ4 phosphorylation via PKA and coupling to a complex that may include prestin can lead to the negative activation and the negative resting potential found in adult OHCs [10].

Regulatory relationships of KCNQ4

• Thyroid hormone receptors TRalpha1 and TRbeta differentially regulate gene expression of Kcnq4 and prestin during final differentiation of outer hair cells [18].

Other interactions of KCNQ4

• Chimeras constructed from different lengths of the KCNQ4 carboxy terminal and the rest KCNQ3 localized a region that confers sensitivity to Ca2+/CaM [15].
• NEM increased the P(o) of KCNQ2, KCNQ4, and KCNQ5 by threefold to fourfold but had no effect on their unitary conductances, suggesting that the increase in macroscopic currents can be accounted for by increases in P(o) [16].
• GJB3 is a member of the connexin gene family and KCNQ4 is a voltage-gated potassium channel [19].
• Co-expression of KCNQ4 and prestin, the OHC motor protein, altered the voltage activation by a further -15 mV [10].
• Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese [20].

Analytical, diagnostic and therapeutic context of KCNQ4

• We have re-examined and extended the expression analyses of KCNQ4 in the murine inner ear using RT-PCR and whole mount in situ hybridization [13].
• Dual immunocytochemistry revealed that KCNQ4 is the major KCNQ channel subunit expressed in all dopaminergic neurons in the mesolimbic and nigrostriatal pathways [21].
• We provide immunofluorescence data showing that Kcnq4 expression in the adult cochlea has both longitudinal (base to apex) and radial (inner to outer hair cells) gradients [4].

References