Date of Award

Spring 5-15-2022

Author's School

McKelvey School of Engineering

Author's Department

Biomedical Engineering

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Voltage-gated sodium channels (NaV) conduct the inward current responsible for the initiation and propagation of the electrical signals in myocytes and neurons, known as action potentials (AP). Precise regulation of cardiac NaV1.5 opening and closing is essential for maintaining a normal heart beat. A disruption of NaV1.5 function, especially of its inactivation after opening, results in inherited cardiac arrhythmias such as Long QT Type 3 (LQT3) syndrome. This pathology is caused by an increase in the late INa that enters myocytes later in the AP and prolongs its duration. Late INa is also enhanced in acquired diseases such as heart failure (HF). NaV channels are regulated by many auxiliary subunits, including intracellular Fibroblast Growth Factors (iFGFs). Each iFGF gene encodes multiple different isoforms, varying in their N-terminal sequences. The interaction between and regulation of iFGF and NaV channels is isoform specific. In this dissertation, I investigated the modulation of cardiac NaV1.5 channels by iFGFs that are highly expressed in human and mouse hearts (FGF12B and FGF13VY). I discovered how the different iFGFs control NaV1.5 voltage sensing and then modulate NaV channel inactivation differently. I also demonstrated that FGF12A, which is upregulated in patients with HF, can convey therapeutic benefits by inhibiting late INa. This result provides new insight into how differential expression of iFGF isoforms can modulate the adverse pharmacological responses that are observed in HF patients prescribed with anti-arrhythmic drugs. Lastly, I present a newly developed tool for studying inactivation dynamics and the interplay between the different components of NaV channel involved in its inactivation, allowing deeper insight into this essential regulatory mechanism.


English (en)


Jonathan R Silva

Committee Members

Jeanne Nerbonne

Included in

Biophysics Commons