Long-term desensitization of nicotinic acetylcholine receptors is regulated via protein kinase A-mediated phosphorylation

Ken Paradiso, Paul Brehm

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

During prolonged application of transmitter, ligand-gated ion channels enter a nonconducting desensitized state. Studies on Torpedo electroplax nicotinic acetylcholine (ACh) receptors have shown that entry into the desensitized state is accelerated by protein kinase A-dependent (PKA) receptor phosphorylation. To examine the effects of phosphorylation on desensitization of muscle-type ACh receptors, we expressed the frog embryonic receptor type in Xenopus oocytes. Treatment of embryonic muscle ACh receptors with 8-Br cAMP had no measurable effect on the rate of entry into a desensitized state, but it greatly accelerated the recovery from desensitization. Three complementary approaches to reduce the levels of receptor phosphorylation provided additional evidence for a role of PKA- dependent phosphorylation in rescuing receptors from longterm desensitization. Inactivation of the endogenous PKA activity by coexpression of an inhibitor protein, treatment of receptors with phosphatase, and removal of phosphorylation sites by site-specific subunit mutation all resulted in slowed recovery. Our findings point to the existence of two distinct desensitized states: one requiring several seconds for full recovery and a second state from which recovery requires minutes. Receptors lacking PKA phosphorylation sites exhibit a pronounced increase in the slowly recovering component of desensitization, suggesting that receptor phosphorylation speeds overall recovery by reducing the entry into a deep desensitized state. This newly described effect of phosphorylation on ACh receptor function may serve as an important modulator of postsynaptic receptor sensitivity.

Original languageEnglish (US)
Pages (from-to)9227-9237
Number of pages11
JournalJournal of Neuroscience
Volume18
Issue number22
DOIs
StatePublished - Nov 15 1998

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • ACh receptor
  • Depression
  • Nicotinic receptors
  • Patch clamp
  • Skeletal muscle
  • Synaptic

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