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Multiple inhibitory G-protein-coupled receptors resist acute desensitization in the presynaptic but not postsynaptic

Reagan L Pennock1, Matthew S Dicken, Shane T Hentges

  • 1Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523, USA.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|July 28, 2012
PubMed

Insights

Presynaptic G(i/o)-coupled receptors resist acute desensitization, unlike their postsynaptic counterparts. This compartment-specific resistance suggests unique modifications protect presynaptic receptor function.

Area of Science:

  • Neuroscience
  • Molecular Pharmacology
  • Cell Biology

Background:

  • G(i/o)-coupled receptors commonly undergo acute desensitization.
  • Recent studies suggest presynaptic μ-opioid receptors (MORs) resist desensitization, unlike somatodendritic or heterologous system expressed MORs.
  • It remains unclear if this differential desensitization applies to other G(i/o)-coupled receptors or within single cell types.

Purpose of the Study:

  • To investigate whether presynaptic and postsynaptic receptors of the same type exhibit differential acute desensitization.
  • To determine if this phenomenon extends to other G(i/o)-coupled receptors beyond MORs.
  • To explore the mechanisms underlying presynaptic receptor resistance to desensitization.

Main Methods:

  • Whole-cell recordings from proopiomelanocortin (POMC) neurons in mouse brain slices.
  • Application of agonists for μ-opioid, nociceptin, and GABA(B) receptors.
  • Optogenetic stimulation (Channelrhodopsin-2) to evoke transmitter release from POMC neuron terminals.
  • Pharmacological knockdown of MORs to assess receptor reserve.

Main Results:

  • Postsynaptic currents induced by agonists desensitized rapidly, while presynaptic inhibition of transmitter release persisted.
  • Light-evoked transmitter release from POMC terminals remained inhibited throughout agonist exposure, confirming presynaptic resistance.
  • Presynaptic GABA(B) receptor desensitization occurred in a subset of recordings, indicating resistance is not an intrinsic terminal property.
  • Receptor reserve depletion did not explain MOR presynaptic resistance.

Conclusions:

  • Presynaptic G(i/o)-coupled receptors (including MORs, nociceptin, and GABA(B)) resist acute desensitization, contrasting with their postsynaptic counterparts.
  • This compartment-specific desensitization resistance is observed within the same neuron type (POMC neurons).
  • A compartment-specific modification, rather than an intrinsic property of the terminal, likely confers presynaptic receptor resistance to desensitization.

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