Conservation of Calcium Regulation Across Voltage-gated Calcium and Sodium Channels

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dc.contributor.advisorYoung, Eric D.en_US
dc.contributor.authorJohny, Manu Benen_US
dc.contributor.committeeMemberYue, David T.en_US
dc.contributor.committeeMemberCaterina, Michael J.en_US
dc.contributor.committeeMemberGabelli, Sandra B.en_US
dc.contributor.committeeMemberTomaselli, Gordon F.en_US
dc.date.accessioned2015-09-16T03:37:13Z
dc.date.available2015-09-16T03:37:13Z
dc.date.created2015-05en_US
dc.date.issued2015-02-19en_US
dc.date.submittedMay 2015en_US
dc.description.abstractThe voltage-gated Ca2+ and Na channels represent two major ion-channel superfamilies with distinct biophysical properties that support diverse and vital physiological functions. Accordingly, these superfamilies have long been studied as distinct entities. That said, the carboxyl tail of these channels exhibit remarkable homology, hinting at a purposeful module long-shared amongst these molecules. If these homologous tail domains elaborated functions of like correspondence, a common origin of such a module might be suggested. For Ca2+ channels, the interaction of CaM with their carboxy-terminus evokes robust and recognizably similar forms of Ca2+ regulation. By contrast, over a decade of research has revealed subtle and variable Ca2+ effects on Na channels, calling into question the very existence of a shared module. Here, using Ca2+ photouncaging, we find that these dissimilarities in Na channels are only apparent, and that Ca2+ regulatory function and mechanism are fundamentally conserved. To identify the molecular states underlying channel regulation, we develop a structure-function approach relating the strength of regulation to the affinity of underlying calmodulin/channel interactions, by a Langmuir relation. By application of this theoretical framework to Ca2+ channels, we uncovered an unprecedented switching of CaM interaction on the channel carboxy-terminus. This system of structural plasticity furnishes a unified mechanistic framework to understand Ca2+ and Na channel regulation and offers shared principles to approach related channelopathic diseases. In all, these results help substantiate the persistence of an ancient Ca2+ regulatory design across channel superfamilies – a relic that has been preserved for much of living history.en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.urihttp://jhir.library.jhu.edu/handle/1774.2/37940
dc.languageen
dc.publisherJohns Hopkins University
dc.subjectcalmodulinen_US
dc.subjectcalcium channelsen_US
dc.subjectsodium channelsen_US
dc.subjection channel regulationen_US
dc.titleConservation of Calcium Regulation Across Voltage-gated Calcium and Sodium Channelsen_US
dc.typeThesisen_US
dc.type.materialtexten_US
thesis.degree.departmentBiomedical Engineeringen_US
thesis.degree.disciplineBiomedical Engineeringen_US
thesis.degree.grantorJohns Hopkins Universityen_US
thesis.degree.grantorSchool of Medicineen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePh.D.en_US
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