RT Journal Article
SR Electronic
T1 Long-Term Desensitization of Nicotinic Acetylcholine Receptors Is Regulated via Protein Kinase A-Mediated Phosphorylation
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9227
OP 9237
DO 10.1523/JNEUROSCI.18-22-09227.1998
VO 18
IS 22
A1 Ken Paradiso
A1 Paul Brehm
YR 1998
UL http://www.jneurosci.org/content/18/22/9227.abstract
AB During prolonged application of transmitter, ligand-gated ion channels enter a nonconducting desensitized state. Studies onTorpedo 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 inXenopus 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 long-term 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.