Abstract

The voltage-gated Nav1.5 channel is responsible for the rapid depolarization of the cardiac action potential. A key feature of the Nav1.5 channel is its rapid activation and inactivation. The C-terminal domain (CTD) of Nav1.5 and subsequent auxiliary subunits that bind there can influence the gating kinetics of Nav1.5. In particular, intracellular fibroblast growth factors (iFGFs) and calmodulin (CaM) both shift the voltage-dependence of inactivation, or steady-state inactivation (SSI), in a depolarizing manner. Recently, a non-canonical CaM binding site was discovered on the A-splice variants of iFGFs. As FGF12A and CaM can interact with each other independent of Nav1.5, a model of how auxiliary subunits systematically affect the Nav1.5 channel is needed. In this dissertation, I examined the mechanisms associated with FGF12A and CaM’s interaction with the Nav1.5 channel. I determined that FGF12A affects Nav1.5 function via two mechanisms: CaM-independent and CaM-dependent. The CaM-independent mechanism of FGF12A involves FGF12A’s canonical role in the prevention of pathogenic INa,L. I demonstrated that the CaM-dependent mechanism of FGF12A alters Nav1.5’s voltage-dependence of inactivation via the VSD-IV. Lastly, I determined that through CaM’s presence on the FGF12A N-terminus, the auxiliary proteins can enforce a Ca2+ sensitivity on Nav1.5’s inactivation previously not described.

Committee Chair

Jonathan Silva

Committee Members

Baranidharan Raman; Baron Chanda; David Ornitz; Jeanne Nerbonne

Degree

Doctor of Philosophy (PhD)

Author's Department

Biomedical Engineering

Author's School

McKelvey School of Engineering

Document Type

Dissertation

Date of Award

6-12-2026

Language

English (en)

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