Structure-Function Relationships and Biochemical Manipulation of 6-TM Superfamily Ion Channels

Open Access
Author:
Pisupati, Aditya
Graduate Program:
Neuroscience
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
July 17, 2018
Committee Members:
  • Timothy J Jegla, Dissertation Advisor/Co-Advisor
  • Timothy J Jegla, Committee Chair/Co-Chair
  • Melissa Rolls, Committee Member
  • Bernhard Luscher, Committee Member
  • William O Hancock, Outside Member
  • Santhosh Girirajan, Committee Member
Keywords:
  • ion channels
  • voltage-gated
  • structure
  • function
  • six-transmembrane
  • 6-TM
  • Shaker
  • CNBD
  • TRPV
Abstract:
The six-transmembrane (6-TM) superfamily of ion channels is a diverse group of tetramer-forming ion channels. Members of this superfamily are regulated by a many different physical and chemical stimuli, including (but not limited to): organic compounds, temperature, mechanical stress, and transmembrane potential. 6-TM channels are critical for regulating neuronal excitability, cardiac pacemaking, sensing of thermal and mechanical stimuli, and maintaining water balance in plants among many other functions. In this thesis, I will first present an overview of 6-TM containing channels. This will be followed by three different projects involving channels from three families within the 6 TM superfamily: Shaker, Transient Receptor Potential Vanilloid (TRPV), and Cyclic Nucleotide Binding Domain (CNBD) channels. The project involving Shaker family channels identifies the stoichiometry of an obligatory heteromeric subunit and determines that this stoichiometry is regulated by a mechanism involving the activation gate. In the TRPV project, C. elegans and D. melanogaster TRPV channels are found to be activated by the vitamin B3 metabolite nicotinamide. In the investigations of CNBD containing channels, it is determined that heme appears to be an evolutionarily conserved regulator of CNBD-containing channels in both plant and animal lineages. Finally, I will discuss where these works fit into our current understanding of ion channels and physiology and will speculate on the outcome of new questions posed by the results of these three projects.