Synaptic Compensatory Mechanism and its Impairment in Autoimmune Myasthenic Diseases
Neurological Center, Kanazawa-Nishi Hospital, Kanazawa, Ishikawa, 920-0025, Japan
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 M1-type 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 thymoma-associated 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.
Post-synaptic organization and its contribution to trans-synaptic communication
In the neuromuscular junction, the presynaptic calcium homeostasis for acetylcholine (ACh) release and the postsynaptic nicotinic ACh receptor (nAChR) clusters anchored to the membrane by rapsyn (immobilized by heat-shock proteins) are modulated by the molecular mechanisms underlying synaptic plasticity.1-4 The former depends on functional organizations including the active zone architecture (piccolo, bassoon, RIM, RIM-BP, ELKS, Munc 13, α-liprin, Munc 18, complexin, Neurexins, etc.), calcium channels, SNARE complex, synaptotagmins, synaptic vesicles and presynaptic autoreceptors5-9; the latter depends on agrin, Wnts (wingless integration site family of glycoproteins), Lrp4 (low-density lipoprotein receptor-related protein 4), MuSK (muscle-specific tyrosine kinase) and Dok 7 (downstream kinase 7).10-18 The postsynaptic structure to be precisely opposed to the nerve terminal is stabilized by the extracellular matrix (including synaptic collagens such as Q, IV and XIII, perlecan, biglycan, laminins and α-dytroglycan) and dystrophin-associated glycoprotein complex (including β-dystroglycan [linking to rapsyn and utophin], cortactin (acting as a synaptic kinase substrate and a regulator of actin polymerization), caveolin 3, coronin 6, α-dystrobrevin (conducted by neuregulin 1-Erb B receptor interaction), and Sorbs 1/2 (conducted by Dok7-Crk-L).19-34
In the trans-synaptic communication (Figure 1), the signals are mediated via (1) the Wnt canonical signaling by way of Wnt-MuSK Ig 4 (cysteine-rich domain)/Dishevelled (scaffold protein)/ inhibition of glycogen synthase kinase 3/β-catenin/Slit 2 in the muscle35-37; (2) muscle-derived Lrp-4 (eight low-density lipoprotein a [LDLa] repeats),38 interacting with an Lrp 4-binding protein in motor neuron38,39 ; (3) muscle laminin β2 tethering the P/Q-type and N-type voltage-gated calcium channels (VGCCs) to the presynaptic active zone via α3 integrin40,41; (4) muscle-derived laminins α4, α5 and β2 in the laminin-network including muscle-agrin.42,43 Neuregulin-1,44 endostatin,45 and bone morphogenic protein pathway members46 have been suggested as candidate retrograde signaling molecules.47
Modes of compensatory vesicle endocytosis in the nerve terminal
The fast-mode of endocytosis (clathrin-independent synaptic vesicle recycling) operates by promoting recruitment of dynamin 1/synaptophysin/synaptobrevin48,49 or by calcium/calmodulin/calcinulin/dynamin signaling (endocytosis overshoot)50;?these mechanisms require a large influx of external calcium.51-54(Figure 1). This homeostatic calcium influx is promoted by the activation of G protein-coupled receptors (GPCRs), such as the presynaptic M1-type muscarinic acetylcholine receptor (mAChR) and adenosine receptor (A2A),55-,57 and the interaction of brain-derived neurotrophic factor (BDNF) with receptor tyrosine kinase (TrkB) in the nerve terminal58,59(Figure 1). The positive effect of calcium influx by the M1-type mAChR-mediated signal is kept in balance with inhibitory presynaptic M2-type mAChR/protein kinase A signaling; the balance is modulated by adenosine (receptors: A2A for activation; A1 for inhibition) and TrkB55-57,60(Figure 1).
The mechanisms for the positive effect of GPCR (M1-type mAChR) and BDNF share a common biological pathway mediated by phospholipase C(PLC)/phosphatidylinositol-4,5-bisphosphate (PIP2)/diacylglycerol(DAG)/protein kinase C (PKC); these biological mechanisms stimulate the P/Q-type voltage-gated calcium channel (VGCC)55,58(Figure 1). The PLC-generated DAG activates the non-voltage-gated calcium-dominant channel (transient receptor potential canonical [TRPC] 3, 6 and 7)61,62 and also regulates the vesicle priming protein (Munc13-1) to recruit ACh containing vesicles for the immediately releasable pool.63(Figure 1). The PLC-generated inositol triphosphate (IP3) interacts with the IP3 receptor; this allows the TRPC-mediated calcium influx to be free from inhibitory control by scaffolding protein, Homer 164(Figure 1). Among the seven members in TRPC family, TRPC3, TRPC6 and TRPC7 are the close homologues; it is structurally confirmed that the TRPC3 is abundantly expressed in the nervous system and has a unique feature with the remarkable long S1-S4 domain stretching into the extracellular side and supporting the formation of the extracellular domain;65 thereby, the TRPC3 could be accessible to antibodies in the manner similar to the M1-type mAChR containing the extracellularly exposed domain.66 The M1-type mAChR is physiologically associated with the non-voltage-gated channel (TRPC)-mediated calcium influx67 (as shown by brown and blue lines with arrow-head in Figure 1). This association may thus be cooperative to act on the mechanism and function compensating synaptic disorders. As mentioned above, however, we should take notice that the large Ca2+ influx for the compensatory presynaptic mechanisms via M1-type mAChR, TRPCs/IP3R and adenosine A2A receptor are controlled (in order to prevent injurious Ca2+-excess in the nerve terminal) by the balance with the inhibitory mechanisms based on M2-type mAChR, Homer 1, adenosine A1 receptor and TrkB.
Figure 1: Schematic presentation of acetylcholine (ACh) release which is upregulated to compensate presynaptic dysfunctions by the homeostatic mechanisms operating in the active zone of the nerve terminal.
Immunology in myasthenia gravis and Lambert-Eaton myasthenic syndrome focusing presynaptic autoreceptors and channels for synaptic compensatory mechanisms
In view of the above-mentioned synaptic physiology, serum samples from myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) were assayed by immunoblotting using the human M1-type mAChR fusion protein,68 and by ELISA using the peptide synthesized based on the sequences of the human TRPC3 (extracellularly exposed segment: Phe611-His640).69 Of 25 MG patients with postsynaptic nAChR antibodies, seven (28 %) were positive for presynaptic M1-type mAChR antibodies,68 and 9 (36 %) were positive for TRPC3 antibodies69 (Table 1). The clinical severity of these patients (graded by Myasthenia Gravis Foundation of America, MGFA, Clinical Classification70) tends toward higher, more severe grades,68,69 suggesting that their synaptic functions may not be adequate to upregulate ACh quantal release to compensate postsynaptic defect.
Reportedly, the electrophysiological study in MG with AChR antibodies showed that the compensatory ACh release upregulation cannot be sustained at the high frequency of nerve stimulation,71 possibly because the reduction in homeostatic small reserve pool of vesicles that depends on presynaptic adenosine A2A receptor operating Ca2+ influx via L-type VGCC.72-74 In a long-tetanic load in muscle, the complex compensatory mechanisms including the presynaptic autoreceptor and channel in this signaling pathway may underlie to compensate postsynaptic dysfunction.
As an additional consideration to the physiological role of TRPC3, it is worthy to note that the TRPC3 takes part in muscle contraction in addition to above-mentioned synaptic transmission. Many of the severe-graded MG patients studied herein have thymoma and are positive for antibodies to the ryanodine receptor 1 (RyR1) (Table 1). RyR1 activates the sarcoplasmic Ca2+ release in the excitation-contraction coupling via membrane-depolarization75; this cooperates with TRPC3 which is activated by PLC-PIP2-DAG signaling pathway76,77 and conducts the activating signal to RyR1 via triadic bridging proteins, including TRPC1 and possibly coregulatory proteins (junctophyins 1 and 2, homer, mitsugumin 29, calreticulin and calmodulin).78,79 In our experiment (Table 1), three synthetic RyR1 peptides were used as antigens to determine antibodies: (1) the residues 1191-1216 (a region toward the N-terminus that faces the loop between domains II and III of dihydropyridine receptor [voltage sensor]),80 (2) the residues 4997-5017 (C-terminal transmembrane segment, which is expressed in thymoma epithelial cells and is suspected of inducing breakdown in tolerance to RyR1),81 and (3) the residues 5019-5038 (C-terminal tail which protrudes into cytoplasm outside the sarcoplasmic reticulum (SR) and can form a functional Ca2+ release channel)82; they were highly positive for antibody-detection particularly by (2) and (3). The experiment using TRPC3-knockdown skeletal myotubes showed that the SR Ca2+ release after direct RyR1 activation by caffeine was decreased regardless of SR Ca2+ content.83,84
Table 1: Clinical and immunological profiles in 25 patients with myasthenia gravis
In LEMS which is often associated with small-cell lung carcinoma (SCLC) expressing antigens immunologically cross-reactive with the nerve terminal proteins, we showed that M1-type mAChR antibodies are implicated in this presynaptic disorder, the pathogenicity of which has mainly referred to the antibodies directing to presynaptic components, P/Q-type VGCC and synaptotagmin 1.85-88 In 25 LEMS patients whose diagnosis was electrophysiologically confirmed (low amplitude of muscle action potential evoked with single nerve stimulation and its marked potentiation after tetanic nerve stimulation), 19 patients (76 %), 4 of whom were negative for antibodies to both P/Q-type VGCC and synaptotagmin 1, were positive for presynaptic M1-type mAChR antibodies68,85,89 (Table 2). Passive transfer of serum IgG from a patient solely positive for presynaptic M1-type mAChR antibodies to mouse produced the electrophysiological features of LEMS (reduced ACh quantal contents confirmed by the microelectrode study).89 The compensatory mechanism that activates presynaptic M1-type mAChR and modulates the fast-mode of synaptic vesicle recycling may be restricted by coincident M1-type mAChR antibodies in LEMS.85,89 Pharmacologically, ACh quantal release is reduced by specific M1-type mAChR blockade in mice at standard ion concentrations without added drugs90; this helps us understand the presynaptic M1-type mAChR-dependent compensatory mechanism and its impairment in immunological synaptic disorders. None of 25 patients with LEMS showed antibodies to TRPC3 (studied as disease control for myasthenia gravis).69
Table 2: Clinical, electrophysiological and immunological profiles in 25 patients with Lambert-Eaton myasthenic syndrome
Thymus in myasthenia gravis and cancer in Lambert-Eaton myasthenic syndrome
The MG thymus play a pivotal role in the pathogenesis of the disease. The hyperplastic MG thymus contains the components necessary for an anti-nAChR immune response including activated autoreactive B and T cells, the antigen-presenting cells, the autoantigen and the activated complement receptors in the epithelial cells.91,92 The thymoma-associated MG brings about the abnormal T cell selection caused by the defective expression of tolerogenic autoimmune regulator (AIRE)-positive thymic medulla, the epithelial cells defective in the expression of HLA class II molecules, the lack or reduction of immune-tolerated AChR-positive myoid cells and the failure to generate CD4+, CD25+ and Fox P3-positive regulatory T cells.93 The mTOR (mammalian target of rapamycin)/Akt (serine/threonine kinase) pathway participates to the cell proliferation associated with thymoma growth.94,95 In the innate and adaptive immunity in MG thymus, the crosstalk between the complement (C5a and C3a) and the Toll-like receptors in thymic epithelial cells causes (1) promoting abnormal B cell activation, leading to ectopic germinal center development; (2) Th1/Th17-related pro-inflammatory cytokine production based on T cells disproportion (Th effector>Th regulator); (3) antigen-presentation by dendritic cells recruited by chemokine (CCL17 and CCL22).95,96 The inflammatory cytokine elevation are brought about by the activation of mitogen-activated protein kinases (MAPKs), transcriptional nuclear factor-κB (NF-κB) and activated protein-1 (AP-1).97 The mAChRs (M1 and M5) expressed in thymocytes and lymphocytes contribute to the regulation of pro-inflammatory cytokine production related to adaptive immunity.98,99 In view of the MG immune pathogenicity, the target-specific immunotherapies are developing; the specific therapies are adapted or in expectation of trial to the MG patients refractory to thymectomy and/or usual immunosuppressants by use of (1) IgG-κ chain targeting CD20 B-cell antibody,100 (2) Complement C5 inhibitors,101,102 (3) antibody to cytotoxic T lymphocyte antigen,103 (4) IL-6 receptor blocker,104 (5) IL-10 modulated human dendritic cells to generate regulatory T cells (to be superior to effector T cells),105 (5) recombinant AChR fragment for antigen-specific removal of AChR antibodies,106 (6) human neonatal Fc receptor blocker,107 (7) selective inhibitor of immunoproteasome,108 and (8) inhibitor of inflammatory factors via TRL2/4-P13K-NFκB signaling.109
The SCLC, which tends to associate with LEMS, expresses mAChRs110 as well as VGCC111-113 and synaptotagmins,114 suggesting that the antibodies to neuronal antigens expressed in SCLC corss-react with those on nerve terminals leading to the neurological defects.115 Besides the functional role as the presynaptic autoreceptor which modulates the synaptic transmission, the mAChRs are expressed in lung cancer and their activation (via the cholinergic autocrine loop expressed in cancer and stimulated by ACh secreted by cancer) provides an effect for cancer growth via the activation in mitogen-activated protein kinase and serine/threonine kinase Akt (involved in the phosphatidylinositol-3 kinase signaling pathway).110,116
The fast-mode of endocytosis (clathrin-independent synaptic vesicle recycling) requires a large influx of external Ca2+ to compensate postsynaptic dysfunction. This homeostatic Ca2+ is promoted by phospholipase C (PLC) activation via the activation of G-protein-coupled receptor, such as the presynaptic M1-type muscarinic acetylcholine receptor (mAChR), and also via the interaction of brain-derived neurotrophic factor (BDNF) with receptor tyrosine kinase (TrkB). These biological mechanisms share a common pathway mediated by PLC/phosphatidylinositol-4,5-bisphosphate (Ptdins (4,5)P2)/diacylglycerol (DAG)/protein kinase C (PKC); these in turn potentiate Ca2+ influx voltage-dependently via DAG/PKC-activated P/Q-type voltage-gated Ca2+ channel [VGCC] and voltage-independently via DAG-activated transient receptor potential canonical (TRPCs). The interaction of inositol-1,4,5-triphosphate (IP3) with IP3 receptor (IP3R) allows the TRPC-mediated Ca2+ influx to be free from the inhibitory control by scaffolding protein, Homer1. DAG also regulates the vesicle priming protein (Munc13-1) to recruit ACh-containing vesicles for immediately releasable pool in the active zone of the nerve terminal. In the physiologic condition, the mechanisms to control Ca2+ influx is based on the balance between the promotive effect by M1-type mAChR and the inhibitory effect by M2-type mAChR (modulated by adenosine and TrkB). The presynaptic architecture including SANREs (synaptobrevin, syntaxin and SNAP-25) and Company are detailed in references 5-9. Retrograde signals (from muscle to nerve) organize the active zone architecture contributing to synaptic vesicle recycling for ACh release. Y1: P/Q-type VGCC antibodies; Y2: antibodies to the extracellularly exposed segment of synaptotagmin 1 (N-terminus) during exocytosis; Y3: antibodies to M1-type mAChR; Y4: antibodies to TRPC3.
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