Diseases of Neuromuscular Junction

Abstract

The congregation of axon terminals (synaptic buttons/presynaptic membranes), muscle end plate (postsynaptic membrane), and the space in between these two structures constitutes the neuromuscular junction (NMJ). The signal transduction occurs from nerve to muscle (neurotransmission) by virtue of various factors. The key player is the organic chemical neurotransmitter, acetylcholine (ACh). ACh is produced in the axons by the choline acetyltransferase (CHAT) enzyme from two compounds choline and acetyl-CoA. The ACh is stored in synaptic vesicles through a specific ACh-H+ exchanger, which couples the influx of ACh to the efflux of H+. Prolyl-endopeptidase-like (PREPL) is a protein that activates clathrin-associated adaptor protein 1 (AP1), utilized by the ACh-H+ exchanger. Depolarization of the terminal axonal membrane results in Ca2+ influx via membrane channels that are sensitive to the depolarization wave created by the axon potential. These channels are called voltage-gated calcium channels (VGCCs). The VGCCs are heteromeric multi-subunit complexes. Classification of VGCCs is based on characteristic voltage activation threshold (high- or low-voltage activated), sequence similarities at the pore-forming α1 subunit (Ca.v1, Ca.v2, or Ca.v3), or pharmacological properties (P/Q, N, L, T, or R). The P/Q-type VGCC is primarily involved in neurotransmitter release from motor nerve terminals [1, 2]. Opening of these channels results in fusion of synaptic vesicles containing ACh with the presynaptic membrane thereby pouring ACh into the synaptic space or synaptic cleft. ACh binds to acetylcholine receptors (AChR). AChR on the motor end plate/postsynaptic membrane of skeletal muscle is a nicotinic-type pentamer composed of 2α, β, δ, and e subunits encoded by CHRNA1, cholinergic receptor nicotinic α1 subunit (chromosome 2q31.1); CHRNB1, cholinergic receptor nicotinic β1 subunit (chromosome 17p13.1); CHRND, cholinergic receptor nicotinic δ subunit (chromosome 2q37.1); and CHRNE, cholinergic receptor nicotinic e subunit (chromosome 17p13.2) genes, respectively. Binding of ACh to AChR causes opening of ion channels that results in diffusion of Na+ and K+ across the membrane with subsequent depolarization. When sufficient channels are opened, the depolarization develops into an action potential when voltage-sensitive Na+ channels are opened. ACh is hydrolyzed by the enzyme acetylcholinesterase (AChE), which is tethered to the basal lamina by a protein called collagen-like tail subunit of asymmetric acetylcholinesterase which is encoded by the COLQ (chromosome 3p25.1) gene. The membrane potential of the presynaptic membrane reverts back to resting state by the opening of voltage-gated potassium channels (VGKC). The VGKC include the Ca2+-activated (KCa), inward-rectifying (KIR), and two-pore (K2P) families [3]. LGI1 (leucine-rich glioma-inactivated 1) and Caspr2 (contactin-associated protein-like 2) are VGKC-associated proteins [4, 5]. LGI1 is a synaptic protein localized to the central nervous system (CNS) whereas Caspr2 is present in both the CNS and peripheral nervous system (PNS) [6]. Glycolipids are organic molecules composed of sugar moieties linked to lipid moiety through glycosidic bonds. The glycosphingolipids contain sphingoid or ceramide as the lipid moiety. Gangliosides are acidic glycosphingolipids with one or more sialic acid residues in their carbohydrate moiety [7]. Svennerholm nomenclature is commonly preferred for naming gangliosides. Gangliosides are present in high concentrations in the presynaptic membranes. N-Glycosylation pathway involves sequential attachment of sugar moieties to an amino acid residue. This step is important for crucial for protein folding and intracellular transport.