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Measuring Nucleotide Binding to Intact, Functional Membrane Proteins in Real Time
Published on: March 11, 2021
Nanomolar ambient ATP decelerates P2X3 receptor kinetics
Alexander Grote1, Michael Hans, Zsolt Boldogkoi
1Institute of Cellular Neurosciences, University of Bonn, Sigmund-Freud-Street 25, 53105 Bonn, Germany.
Neuropharmacology
|September 5, 2008
Summary
Persistent low adenosine triphosphate (ATP) concentrations prime P2X3 receptors, slowing their activation and decay. This ATP priming affects pain signaling by modulating P2X3 receptor kinetics.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Homomeric P2X receptors, particularly P2X3 receptors, are crucial in pain signaling pathways.
- Low extracellular adenosine triphosphate (ATP) concentrations can modulate P2X3 receptor activity, affecting current amplitudes through various mechanisms.
- Existing knowledge suggests ATP can enhance or reduce P2X3 receptor currents, but its effect on receptor kinetics was unclear.
Purpose of the Study:
- To investigate the novel phenomenon of ambient low ATP influencing P2X3 receptor kinetics.
- To determine if persistent low ATP affects the activation and decay rates of P2X3 receptor currents.
- To elucidate the underlying mechanism of ATP-mediated modulation of P2X3 receptor kinetics.
Main Methods:
- HEK cell electrophysiology to study P2X3 receptor-mediated currents after pre-application of low ATP.
- UV-flash photolysis of ATP to assess the impact of submicromolar ATP on receptor activation kinetics.
- Validation using native P2X3 receptors from freshly isolated rat dorsal root ganglion neurons.
Main Results:
- Persistent low ATP concentrations significantly decelerated both the activation and decay phases of P2X3 receptor currents.
- This observed 'priming' effect on kinetics differs from previously described high-affinity desensitization (HAD).
- A potential mechanism involves pre-opening receptor isomerization due to occupation of a high-affinity binding site at the resting state.
Conclusions:
- Ambient low ATP acts as a priming agent, modulating P2X3 receptor kinetics rather than just current amplitude.
- This kinetic modulation, distinct from HAD, suggests a physiological fine-tuning mechanism in nociception.
- The findings highlight the role of resting-state ATP levels in regulating the dynamic behavior of P2X3 receptors in pain pathways.
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