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TRPV1 activation power can switch an action mode for its polypeptide ligands
Maxim V Nikolaev1, Natalia A Dorofeeva1, Margarita S Komarova1
1I.M.Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, St.Petersburg, Russia.
Plos One
|May 6, 2017
Summary
Sea anemone polypeptides (APHCs) show bimodal action on TRPV1 receptors, potentiating weak responses and inhibiting strong ones. This suggests a novel therapeutic mechanism for TRPV1-related conditions.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Transient Receptor Potential Vanilloid 1 (TRPV1) receptors mediate pain and temperature sensation.
- TRPV1 activation is modulated by various stimuli and ligands, exhibiting complex, stimulus-dependent behaviors.
- Understanding TRPV1 ligand interactions is crucial for developing targeted therapeutics.
Purpose of the Study:
- To investigate the action of sea anemone polypeptides (APHC1, APHC2, APHC3) on rat TRPV1 receptors.
- To characterize the stimulus-dependent effects of APHCs on TRPV1 activation.
- To elucidate the potential binding site and mechanism of action of APHCs on TRPV1.
Main Methods:
- Electrophysiological recordings of TRPV1 channel activity.
- Fluorescent calcium (Ca2+) imaging to measure cellular responses.
- Molecular modeling to predict ligand-receptor interactions.
Main Results:
- APHCs exhibited bimodal activity, potentiating TRPV1 responses to low capsaicin concentrations but inhibiting responses to high concentrations.
- This bimodal action was also observed for other TRPV1 activators like 2APB and protons (acidification).
- Molecular modeling suggested a binding site on the outer loops of TRPV1, potentially allosterically linked to the capsaicin binding site.
Conclusions:
- APHCs display a unique activity-dependent, bimodal modulation of TRPV1.
- The findings support a double-gate model where APHCs may stabilize an intermediate receptor state.
- These results offer insights into novel TRPV1 ligand interactions with therapeutic potential.
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