Antibody to acetylcholine receptor increases degradation of junctional and extrajunctional receptors in adult muscle

Abstract

MYASTHENIA gravis is a disease of impaired neuromuscular transmission (for review see ref. 1), which probably results from a reduced number of acetylcholine (ACh) receptors in the muscle membrane². Myasthenia is thought to be an autoimmune disease¹, in part because most myasthenia patients have circulating antibody to the receptor^3,4. Specific antibodies can increase the turnover and reduce the amount of surface proteins⁵, including ACh receptors^6–8, on cells in tissue culture. Because such an effect could contribute to the decrease of ACh receptors found in myasthenia, we have investigated the effect of anti-receptor antibodies on the turnover of ACh receptors in innervated and denervated muscles of adult rats. Two forms of ACh receptor are found in mammalian muscle. Junctional receptors are densely packed and highly localised at motor endplates^9–11, while extrajunctional receptors are found in developing and denervated adult muscles at low density over the entire muscle surface^10–12. The two forms of receptors are almost identical molecules but can be distinguished both in situ and after purification (for discussion, see ref. 13). Differences in isoelectric point¹⁴ and immunological properties (ref. 15 and unpublished results of C.B.W. and Z.W.H.) suggest that they have slight structural differences. One important difference between these forms of receptors is their stability in the membrane. Extrajunctional receptors undergo continual turnover with a half-life of about 14–18 h in both developing and denervated adult muscles^16–18. In contrast junctional receptors are much more stable and have not previously been shown to turn over, although their half-life in vivo has been estimated to exceed 6 d (refs 16 and 18). We report here that junctional receptors can turn over and that antireceptor antibodies increase the degradation of both junctional and extrajunctional receptors in adult muscle.