Return to search

Functional Characterization of Na+/Ca2+ Exchangers in Caenorhabditis elegans

<p> Na<sup>+</sup>/Ca<sup>2+</sup> exchangers are low affinity/high capacity transporters that mediate Ca<sup>2+</sup> extrusion by coupling Ca<sup>2+</sup> efflux to the influx of Na<sup>+</sup> ions. Their primary function is to maintain Ca<sup>2+</sup> homeostasis in cells of all organisms and they play a particularly important role in excitable cells that experience transient Ca<sup>2+</sup> fluxes. While their functions have been studied extensively in muscle cells, much is still unknown about their contributions to the nervous system. Data suggests that Na<sup>+</sup>/Ca<sup> 2+</sup> exchangers play a key role in neuronal processes such as memory formation, learning, oligodendrocyte differentiation and axon guidance. They are also implicated in pathologies such as Alzheimer&rsquo;s Disease, Parkinson&rsquo;s Disease, Multiple Sclerosis and Epilepsy. While they are implicated in critical neuronal processes, a clear understanding of their mechanism remains unknown. This dissertation examines the role of Na<sup>+</sup>/Ca<sup>2+</sup> exchangers in the invertebrate model organism <i>Caenorhabditis elegans </i>. There are ten identified Na<sup>+</sup>/Ca<sup>2+</sup> exchanger genes in <i>C. elegans</i> (labeled <i>ncx-1</i> to <i>ncx</i>-10). Data presented here is the first comprehensive description of their genetics and function in <i>C. elegans</i>. The expression pattern of all 10 Na<sup>+</sup>/Ca<sup>2+</sup> exchanger genes is described and their phylogeny is examined comparatively across humans and flies. Analysis of <i>ncx-2</i> and <i>ncx-8</i> mutants shows important roles for Na<sup>+</sup>/Ca<sup>2+</sup> exchanger genes in egg-laying, lipid storage and longevity, suggesting a role in diverse biological functions for Na<sup>+</sup>/Ca<sup>2+</sup> exchangers in <i>C. elegans</i>. The function of an NCLX type Na<sup>+</sup>/Ca<sup> 2+</sup> exchanger NCX-9 is also detailed comprehensively. Analysis of <i> ncx-9</i> mutants shows that NCX-9 is required for asymmetrical axon guidance choices made by the DD and VD GABAergic motor neuron circuit. Pathway analysis shows that NCX-9 regulates asymmetric circuit patterning through RAC-dependent UNC-6/Netrin signaling and LON-2/Glypican Heparan Sulfate signaling. <i> In vitro</i> analysis of NCX-9 physiology in HEK cells shows that NCX-9 is a mitochondrial Na<sup>+</sup>/Ca<sup>2+</sup> exchanger, similar to NCLX, which is its homolog in humans.</p>

Identiferoai:union.ndltd.org:PROQUEST/oai:pqdtoai.proquest.com:10262140
Date08 April 2017
CreatorsSharma, Vishal
PublisherThe George Washington University
Source SetsProQuest.com
LanguageEnglish
Detected LanguageEnglish
Typethesis

Page generated in 0.002 seconds