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XB-ART-49438
J Invest Dermatol April 1, 2015; 135 (4): 1033-1042.
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Aberrant connexin26 hemichannels underlying keratitis-ichthyosis-deafness syndrome are potently inhibited by mefloquine.

Levit NA , Sellitto C , Wang HZ , Li L , Srinivas M , Brink PR , White TW .


Abstract
Keratitis-ichthyosis-deafness (KID) syndrome is an ectodermal dysplasia caused by dominant mutations of connexin26 (Cx26). Loss of Cx26 function causes nonsyndromic sensorineural deafness, without consequence in the epidermis. Functional analyses have revealed that a majority of KID-causing mutations confer a novel expansion of hemichannel activity, mediated by connexin channels in a nonjunctional configuration. Inappropriate Cx26 hemichannel opening is hypothesized to compromise keratinocyte integrity and epidermal homeostasis. Pharmacological modulators of Cx26 are needed to assess the pathomechanistic involvement of hemichannels in the development of hyperkeratosis in KID syndrome. We have used electrophysiological assays to evaluate small-molecule analogs of quinine for suppressive effects on aberrant hemichannel currents elicited by KID mutations. Here, we show that mefloquine (MFQ) inhibits several mutant hemichannel forms implicated in KID syndrome when expressed in Xenopus laevis oocytes (IC50∼16 μM), using an extracellular divalent cation, zinc (Zn(++)), as a nonspecific positive control for comparison (IC50∼3 μM). Furthermore, we used freshly isolated transgenic keratinocytes to show that micromolar concentrations of MFQ attenuated increased macroscopic membrane currents in primary mouse keratinocytes expressing human Cx26-G45E, a mutation that causes a lethal form of KID syndrome.

PubMed ID: 25229253
PMC ID: PMC4363291
Article link: J Invest Dermatol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: gjb2 kif22
GO keywords: gap junction hemi-channel activity

Disease Ontology terms: autosomal dominant keratitis-ichthyosis-deafness syndrome
OMIMs: KERATITIS-ICHTHYOSIS-DEAFNESS SYNDROME, AUTOSOMAL DOMINANT; KIDAD

Article Images: [+] show captions
References [+] :
Barrio, Gap junctions formed by connexins 26 and 32 alone and in combination are differently affected by applied voltage. 1991, Pubmed, Xenbase