Arsenic Alter Cell to Cell Communication by Directly Binding to Gap Junction Protein Connexin 43

Babu, Swathy (2016) Arsenic Alter Cell to Cell Communication by Directly Binding to Gap Junction Protein Connexin 43. Masters thesis, Indian Institute of Science Education and Research Kolkata.

PDF (MS dissertation of Swathy Babu (11MS024)) Swathy_Babu_11024__BS_MS_Thesis.pdf - Submitted Version Restricted to Repository staff only Download (1MB)

Abstract

Arsenic contaminated drinking water has been a major cause of concern from both the human health and environmental standpoints. Arsenic exposure has been linked to several types of cancer, including skin, lung, liver, and bladder. Chronic exposure of Arsenic is also known to cause diabetes mellitus, cardiovascular abnormalities, nephrotoxicity and neurotoxicity. Arsenic has been found to bind proteins in the cells which can result in conformation changes resulting in malfunctioning of such proteins. Very recently in one of our studies we have observed that Arsenic alters cell to cell communication by altering the trafficking of gap junction protein connexin 43 (Cx43). Cx43 is one of the most abundant gap junction proteins present in most of the cells. Gap junctions are one of the interconnections which form a direct link to enable the diffusion of small aqueous molecules and ions from one cell to its nearest neighbor. Cell to cell communication is an important event required for the survival of living things. The disruption of cell communication can result in uncontrolled cell growth, often leading to cancer. My study is focused to understand whether alteration of gap junction protein Cx43 is specific to Arsenic or is it a general phenomenon of heavy metal toxicity and to decipher the underlying mechanism of Arsenic toxicity, both in vitro and in vivo. Towards this goal my findings revealed that the reduction of Cx43 protein is specific for Arsenic, since the same was not observed with another heavy metal Mercury. Also Inductively coupled plasma mass spectrometry (ICPMS) data demonstrated that Arsenic is entering inside the cell as well as ICPMS studies along with immunoprecipitation of Cx43 revealed that Arsenic can directly bind with Cx43. Cx43 has three cysteine residues in its extracellular loops which give the potential ability for Arsenic to bind and cause conformational change. Experiments are underway by molecular modeling to prove the concept. In addition to that my studies demonstrated that Arsenic treatment can also alter the trafficking of Cx43 to cell surface which in turn reducing functional gap junctions by retaining Cx43 in intracellular compartments in fibroblast cell lines which express endogenous Cx43. More over my extended in vivo studies in mice model also revealed that mice fed with Arsenic in drinking water showed a reduction in Cx43 protein expression in Lung tissues. Taking my current studies together it may shed light in understanding the Arsenic induced alteration of cell to cell communication, which may play a major role in Arsenic induced carcinogenesis.

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