title: Aberrant connexin26 hemichannels underlying keratitis-ichthyosis-deafness syndrome are potently inhibited by mefloquine.
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.
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Noah A
authors.initials: NA
authors.lastname: Levit
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Caterina
authors.initials: C
authors.lastname: Sellitto
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Hong-Zhan
authors.initials: HZ
authors.lastname: Wang
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Leping
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biological and Vision Sciences, SUNY College of Optometry, New York, USA.
authors.forename: Miduturu
authors.initials: M
authors.lastname: Srinivas
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Brink
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA. Electronic address: thomas.white@stonybrook.edu.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: White
mesh_terms: D000818:Animals; D002412:Cations; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D004594:Electrophysiology; D004817:Epidermis / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D020128:Inhibitory Concentration 50; D015603:Keratinocytes / Q000166:cytology; D007634:Keratitis / Q000378:metabolism; D015767:Mefloquine / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009865:Oocytes / Q000166:cytology; D018408:Patch-Clamp Techniques; D014981:Xenopus; D014982:Xenopus laevis; D015032:Zinc / Q000737:chemistry
chemical_list: D002412:Cations; D017630:Connexins; C000607045:GJB2 protein, Xenopus; C000607042:GJB2 protein, human; D000072259:Connexin 26; D015032:Zinc; D015767:Mefloquine