KCNQ (Kv7) K+ channels

KCNQ (Kv7) K+ channels

We have previously identified KCNQ2,3,4 and 5 as novel members of the voltage-gated K+ channel superfamily [28, 29, 30] and have shown that mutations in KCNQ2 and KCNQ3, which can form heteromeric channels [31], may lead to neonatal epilepsy [28]. KCNQ2, KCNQ3, and KCNQ5 mediate neuronal M-currents, a highly regulated potassium current that is already active at resting potentials and that sensitively regulates neuronal excitability. We  also showed that KCNQ4 is mutated in a form of dominant deafness [29]. It is expressed in sensory hair cells of the inner ear [32]. We generated mouse models for KCNQ4 to elucidate its role in human deafness [33]. Some KCNQ K+ channels can associate with ß-subunits of the KCNE family. We showed that KCNE3 abolishes the gating of KCNQ1 channels [34] and, using a KCNE3 KO mouse, demonstrated that KCNQ1/KCNE3 heteromers are important for Cl- secretion in the intestine [35].

Then we investigated the roles of KCNQ4 and KCNQ5 in the vestibular organ using genetic mouse models [36]. Although both channel proteins accumulate at the calyx synapse of vestibular hair cells, both channels are located in the postsynaptic membrane, in contrast to the presynaptic localization of KCNQ4 in cochlear outer hair cells [32]. The importance of KCNQ channels in vestibular function was demonstrated by abnormal vestibule-ocular reflexes.

In addition to the cochlea and the vestibular organ, KCNQ4 is also expressed in selected nuclei of the brainstem, including the auditory pathway and trigeminal ganglia [32]. It is also expressed in a small fraction of large diameter dorsal root ganglion neurons [37]. We showed that it is specifically expressed in rapidly adapting mechanosensors in the skin. Disruption of KCNQ4 severely impairs the frequency tuning of these receptors in mice, as well as in deaf patients carrying KCNQ4 mutations [37]. By contrast, we found that KCNQ2 and KCNQ3 are expressed in very rapidly inactivating D-hair mechanoreceptors and modulate their sensitivity [39].