Stabilization of acetylcholine receptors at the neuromuscular synapse: the role of the nerve.
The majority of acetylcholine receptors (AChRs) at innervated neuromuscular junctions (NMJs) are stable, with half-lives averaging about 11 days in rodent muscles. In addition to the stable AChRs, approximately 18% of AChRs at these innervated junctions are rapidly turned over (RTOs), with half lives of less than 24 h. We have postulated that RTOs may be precursors of stable AChRs, and that the motor nerve may influence their stabilization. This hypothesis was tested by: (i) labeling AChRs in mouse sternomastoid (SM) muscles with 125I-alpha-BuTx; (ii) denervating one SM muscle in each mouse, and (iii) following the fate of the labeled AChRs through a 5-day period when RTOs were either stabilized or degraded. The hypothesis predicts that denervation should preclude stabilization of RTOs, resulting in a deficit of stable AChRs in denervated muscles. The results showed a highly significant (P less than 0.002) deficit of stable AChRs in denervated as compared with innervated muscles. Control experiments excluded the possibility that this deficit could be attributed to independent accelerated degradation of either RTOs or pre-existing stable AChRs. The observed deficit was quantitatively consistent with the deficit predicted by a mathematical model based on interruption of stabilization following denervation. We conclude that: (i) the observed deficit after denervation of NMJs is due to failure of stabilization of pre-existing RTOs; (ii) RTOs at normally innervated NMJs are precursors of stable AChRs; (iii) stabilization occurs after the insertion of AChRs at NMJs, and (iv) motor nerves play a key role in stabilization of RTOs. The concept of receptor stabilization has important implications for understanding the biology of the neuromuscular junction and post-synaptic plasticity.
Ramsay
D A
DA
Department of Neuropathology, Victoria Hospital, London, Ont., Canada.
Drachman
D B
DB
Drachman
R J
RJ
Stanley
E F
EF
D000818:Animals; D002038:Bungarotoxins / Q000378:metabolism; D005260:Female; D007700:Kinetics; D008433:Mathematics; D051379:Mice; D008959:Models, Neurological; D009121:Muscle Denervation; D009132:Muscles / Q000294:innervation*; D009469:Neuromuscular Junction / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000378:metabolism*; D012044:Regression Analysis; D013569:Synapses / Q000502:physiology*; D013997:Time Factors
D002038:Bungarotoxins; D011950:Receptors, Cholinergic