Synaptic Compensatory Mechanism and its Impairment in Autoimmune Myasthenic Diseases

The neuromuscular junction (NMJ) is organized by a complex architecture and various signals orchestrated by sophisticated interactions. They include the presynaptic Ca2+ homeostasis for acetylcholine (ACh) release in the active zone organization, the post-synaptic ACh receptor (AChR) clustering at endplate membranes, the trans-synaptic communication from muscle to nerve, and the synaptic stabilization. The present data and discussions are concerned in an adaptive change of ACh release from the nerve terminal and its immunological impairment in the post-synaptic disease (myasthenia gravis, MG) and the presynaptic disease (Lambert-Eaton myasthenic syndrome, LEMS). Discussions mainly focus the antibody-induced failure of the synaptic compensatory mechanisms that are brought about by the presynaptic autoreceptors (the M1type muscarinic AChR [mAChR] cooperated with adenosine receptors), and the non-voltage-gated Ca2+-dominant influx channel (transient receptor potential canonical [TRPCs], particularly its phenotype TRPC3). Besides the synaptic transmission fatigue, the TRPC3 antibodies are discussed in terms of their implication in the muscle contraction fatigue that often occurs in the thymomaassociated MG and reflects a defect in the physiological association of TRPC3 with the ryanodine receptor-1 in the excitation-contraction coupling in which the sarcoplasmic Ca2+ release takes place. In addition to the modulating role in the NMJ functions, the mAChRs participate in the innate and adaptive inmmunity by MG thymus and in the lung cancer (often associated with LEMS) growth. Synaptic Compensatory Mechanism and its Impairment in Autoimmune Myasthenic Diseases