Noah A. Levit
B.S. Boston University, 2007
Ph.D. Stony Brook University, 2014
8th Year MSTP; 4th Year Medical Student
Advisor: Thomas White, PhD
Department: Physiology & Biophysics, Stony Brook Univ.
Graduate Program: Physiology & Biophysics
Title: Aberrant Cx26 hemichannel activity underlying keratitis-ichthyosis-deafness syndrome
Abstract:
Keratitis-ichthyosis-deafness (KID) syndrome is an ectodermal dysplasia caused by dominant mutations of connexin26 (Cx26). Loss of Cx26 function causes non-syndromic 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 non-junctional 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 inhibits several mutant hemichannel forms implicated in KID syndrome with high affinity when expressed in Xenopus laevis oocytes (IC50˜16µM), using an extracellular divalent cation, zinc (Zn++), as a non-specific positive control for comparison (IC50˜3µM). Furthermore, we used freshly isolated transgenic keratinocytes to show that micromolar concentrations of mefloquine attenuated keratinocytes expressing syndrome. increased human C macroscopic x26-G45E, a membrane mutation lin currents ked to a in let primary hal form mouse of KID syndrome.
Publications:
(pre-MSTP publications indicated with an *)
*Levit NA, Sellitto C, Wang HZ, Li L, Srinivas M, Brink PR, White TW. Aberrant Connexin26 Hemichannels Underlying Keratitis-Ichthyosis-Deafness Syndrome Are Potently Inhibited by Mefloquine. J Invest Dermatol. 2014 Sep 17. doi: 10.1038/jid.2014.408. [Epub ahead of print] PMID: 25229253
*Mhaske PV, Levit NA, Li L, Wang HZ, Lee JR, Shuja Z, Brink PR, White TW. The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity. Am J Physiol Cell Physiol. 2013 Jun 15;304(12):C1150-8. doi: 10.1152/ajpcell.00374.2012. Epub 2013 Feb 27. PMID: 23447037
*Levit NA, Mese G, Basaly MG, White TW. Pathological hemichannels associated with human Cx26 mutations causing Keratitis-Ichthyosis-Deafness syndrome. Biochim Biophys Acta. 2012 Aug;1818(8):2014-9. doi: 10.1016/j.bbamem.2011.09.003. Epub 2011 Sep 10. Review. PMID: 21933663
Wu C, Sodickson A, Cai T, Levit NA, Steigner ML, Rybicki FJ, Ledbetter SM. Comparison of respiratory motion artifact from craniocaudal versus caudocranial scanning with 64-MDCT pulmonary angiography. AJR Am J Roentgenol. 2010 Jul;195(1):155-9. doi: 10.2214/AJR.09.3673. PMID: 20566810 Steigner ML, Mitsouras D, Whitmore AG, Otero HJ, Wang C, Buckley O, Levit NA, Hussain AZ, Cai T, Mather RT, Smedby O, DiCarli MF, Rybicki FJ. Iodinated contrast opacification gradients in normal coronary arteries imaged with prospectively ECG-gated single heart beat 320-detector row computed tomography. Circ Cardiovasc Imaging. 2010 Mar;3(2):179-86. doi: 10.1161/CIRCIMAGING.109.854307. Epub 2009 Dec 31. PMID: 20044512
Steigner ML, Otero HJ, Cai T, Mitsouras D, Nallamshetty L, Whitmore AG, Ersoy H,Levit NA, Di Carli MF, Rybicki FJ. Narrowing the phase window width in prospectively ECG-gated single heart beat 320-detector row coronary CT angiography. Int J Cardiovasc Imaging. 2009 Jan;25(1):85-90. doi: 10.1007/s10554-008-9347-8. Epub 2008 Jul 29. PMID: 18663599
Lu MT, Cai T, Ersoy H, Whitmore AG, Levit NA, Goldhaber SZ, Rybicki FJ. Comparison of ECG-gated versus non-gated CT ventricular measurements in thirty patients with acute pulmonary embolism. Int J Cardiovasc Imaging. 2009 Jan;25(1):101-7. doi: 10.1007/s10554008-9342-0. Epub 2008 Jul 15. PMID: 18626787
