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Understanding the structural basis of slow inactivation in voltage-gated sodium channel

Chatterjee, Soumili
http://orcid.org/0000-0002-4225-6712
http://rave.ohiolink.edu/etdc/view?acc_num=case1544547526420799

Abstract Details

, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Slow inactivation in voltage-gated sodium channels (NaV) directly regulates the excitability of neurons, cardiac myocytes, and skeletal muscles. Although NaV slow inactivation appears to be conserved across phylogenies – from bacteria to humans – the structural basis for this mechanism remains unclear. Using site-directed labeling and EPR spectroscopic measurements of membrane reconstituted prokaryotic NaV homologues, I characterized the conformational dynamics of the selectivity filter region in the conductive and slow-inactivated states in order to determine the molecular events underlying NaV gating. The S4-S5 linker couples the voltage sensor and pore domain in voltage-gated sodium channel and is known to play essential role in electromechanical coupling and channel gating. However, limited information is available on the dynamics of this amphipathic S4-S5 linker during activation and slow inactivation process. In order to understand the molecular events underlying the VSD activation-coupled slow-inactivation in Nav, I used site-directed labeling and EPR spectroscopic measurements of membrane reconstituted prokaryotic NaV homologues to characterize the conformational dynamics of the S4-S5 linker region in the resting and slow-inactivated states by varying the lipid environment. My findings reveal profound conformational flexibility of the pore in the slow-inactivated state. I found that the P1 and P2 pore helices undergo opposing movements with respect to the pore-axis. These movements result in changes in volume of both the central and inter-subunit cavities, which form pathways for lipophilic drugs that modulate slow inactivation. My study also reveals high conformational flexibility of the S4-S5 linker region in slow inactivated conformation and also displays that S4-S5 linker undergoes spatial rearrangement with a radial translation during slow inactivation process. Overall, these findings provide the structural basis and dynamics of slow inactivation gating and provide novel insight into the molecular basis for state-dependent effects of lipophilic and hydrophilic drugs on channel function.
Sudha Chakrapani, Dr. (Advisor)
Physiology

Recommended Citations

Citations

  • Chatterjee, S. (2018). Understanding the structural basis of slow inactivation in voltage-gated sodium channel [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1544547526420799

    APA Style (7th edition)

  • Chatterjee, Soumili. Understanding the structural basis of slow inactivation in voltage-gated sodium channel. 2018. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1544547526420799.

    MLA Style (8th edition)

  • Chatterjee, Soumili. "Understanding the structural basis of slow inactivation in voltage-gated sodium channel." Doctoral dissertation, Case Western Reserve University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1544547526420799

    Chicago Manual of Style (17th edition)

case1544547526420799
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© 2018, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.