Membrane-protein interactions regulate excitability through potassium and chloride channels

Overview & Synopsis

Proteins do not act alone but they assemble dynamically into protein complexes within the cell. Ion channel complexes are made up of an α-pore-forming-subunit associated with specific auxiliary (β) subunits and regulatory proteins. Determination of the molecular identity ofsubunits composing a protein complex is essential to understand the function and regulation of ion channels. During my thesis, I addressed the specificity of auxiliary subunits regarding to the α-pore-forming-subunit. More specifically, I studied the ability of KCNE1, classicallyconsidered as a β-subunit of the cardiac KCNQ1 pore-forming subunit belonging to the voltage-dependent Kv channel superfamily, to regulate the anoctamin superfamily channel TMEM16A, a Ca2+-activated Cl- channel. I found that KCNE1 fulfils all criteria of a bona fide auxiliarysubunit of TMEM16A chloride channels. KCNE1 serves then as a β-subunit for two different superfamilies of ion channels phylogenetically unrelated. In the second part of my thesis, I studied the involvement of protein complexes in analgesia induced by mycolactone, a toxinsecreted by Mycobacterium ulcerans. I found that the angiotensin II receptor 2, by being directly coupled to the two-pore-domain potassium channel TRAAK, increases the channel activity upon mycolactone binding, independently of the canonical G protein signaling pathway. All in all, the obtained results break the dogmatic specificity of auxiliary subunits regarding protein complexes questioning ion channels classification and open the doors to the development of new analgesic molecules.