Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology

Supervisor

Dr. Donglin Bai

Abstract

Mutations in GJA5 encoding the gap junction protein connexin40 (Cx40) have been linked to lone atrial fibrillation (AF). Some of these mutants result in impaired gap junction function due to either abnormal connexin localization or impaired gap junction channels, which may play a role in promoting AF. However, the effects of the AF-linked Cx40 mutants on hemichannel function has not been studied. Here we investigated two AF-linked germline Cx40 mutants, V85I and L221I. These two mutants formed putative gap junction plaques at cell-cell interfaces, with similar gap junction coupling conductance as that of wild-type Cx40. Connexin deficient HeLa cells expressing either of these two mutants displayed prominent propidium iodide (PI)-uptake distinct from cells expressing wild-type Cx40 or other AF-linked Cx40 mutants, I75F, L229M and Q49X. The PI-uptake was sensitive to [Ca2+]o and carbenoxolone, but was not affected by probenecid, indicating that uptake is mediated via connexin hemichannels. A gain-of-hemichannel function in these two AF-linked Cx40 mutants may provide a novel mechanism underlying the etiology of AF.


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