Voltage-sensing mechanisms of ION channels in dynamic lipid membranes
Active Project Grant Awarded Last action
- Award ID
- R35GM154778
- Recipient
-
Saint Louis University UEI JNBLLTBTLLD8
- Awarding agency
-
National Institute of General Medical Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $1,515,000
Award facts
- Assistance listing
- 93.859 Biomedical Research and Research Training
- Completion date 47% complete
- Place of performance
- St. Louis, MO 63104, USA
Award details come from USAspending.gov.
Description
- Abstract
- ION channels in the voltage-gated ION channel (vgic) superfamily play pivotal roles in virtually all physiological processes. This proposal delves into essential constituents of this superfamily, focusing on elucidating the mechanisms governing voltage sensing and electromechanical coupling of these proteins in pathophysiological contexts. Our investigation focuses on discerning the regulatory interplay between the voltage-sensing domain (VSD) of vgics and the lipid-ordered membrane domain (OMD) enriched with cholesterol. Recent findings from our laboratory have unraveled the significant influence of OMD on modulating membrane excitability in somatosensory dorsal root ganglion (DRG) neurons. A reduction in OMD dimensions, leading to augmented native ionic currents of pacemaker hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, emerges as a contributing factor in neuropathic pain and inflammatory pain. These distinct lipid nanodomains exercise direct control over the voltage sensor of HCN channels, consequently influencing channel opening. This aspect of HCN channel regulation, integral to neuronal excitability and cardiac pacemaking, necessitates in-depth investigation. Our biophysical approach employs patch-clamp fluorometry (PCF) combined with fluorescence lifetime imaging microscopy (flim) to measure voltage-sensor conformational dynamics within native lipid environments. Leveraging genetic-code expansion featuring noncanonical amino acids and BIO- orthogonal fluorescence labeling through click chemistry enables site-specific labeling and facilitates förster resonance energy transfer (fret) measurements. Furthermore, our approach includes an improved transition metal fret (tmfret) technique in conjunction with phasor plot flim, with the primary goal of investigating the potential intermediate states of vgic voltage sensors. By successfully implementing this approach, we intend to discern the influence of OMD localization, lipid composition, and disease-associated mutations on these intermediate voltage sensor states. This extensive investigation holds the promise of significantly deepening our understanding of the voltage-sensing mechanism of vgic in physiological processes.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $378,750 | |
| Amendment | $378,750 | |
| Amendment | $378,750 | |
| Original award | $378,750 |
Quick answers
Who received award R35GM154778?
R35GM154778 was awarded to Saint Louis University by National Institute of General Medical Sciences (National Institutes of Health) on July 15, 2024.
How much is award R35GM154778 worth?
$1,515,000 has been obligated on R35GM154778.
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