Adenosine Receptors in Developing and Adult Mouse Neuromuscular Junctions and Functional Links With Other Metabotropic Receptor Pathways

Abstract

In the last few years, we have studied the presence and involvement in synaptogenesis and mature transmitter release of the adenosine autoreceptors (AR) in the mammalian neuromuscular junction (NMJ). Here, we review and bring together the previously published data to emphasize the relevance of these receptors for developmental axonal competition, synaptic loss and mature NMJ functional modulation. However, in addition to AR, activity-dependent mediators originating from any of the three cells that make the synapse (nerve, muscle, and glial cells) cross the extracellular cleft to generate signals in target metabotropic receptors. Thus, the integrated interpretation of the complementary function of all these receptors is needed. We previously studied, in the NMJ, the links of AR with mAChR and the neurotrophin receptor TrkB in the control of synapse elimination and transmitter release. We conclude that AR cooperate with these receptors through synergistic and antagonistic effects in the developmental synapse elimination process. In the adult NMJ, this cooperation is manifested so as that the functional integrity of a given receptor group depends on the other receptors operating normally (i.e., the functional integrity of mAChR depends on AR operating normally). These observations underlie the relevance of AR in the NMJ function.

Opposed Actions of PKA Isozymes (RI and RII) and PKC Isoforms (cPKCβI and nPKCε) in Neuromuscular Developmental Synapse Elimination

“…Another regulator of PKA is A 2A adenosine receptor signaling, which has the opposite effect to M 2 signaling. It stimulates adenyl cyclase and PKA activity [29,59,68]. Thus, the A 2A -mediated increased PKA activity can be expected to cause a delay in axon loss similar to the one observed here when PKA was experimentally directly activated.…”

“…In the NMJ, activity dependent variations of released mediators such as Ach, adenosine, and neurotrophins are sensed by presynaptic mAChR, AR (P1), and the TrkB receptors [17,54,55], as well as ATP receptors (P2) and glutamate receptors [18,19,56,57]. These receptors are coupled to downstream kinases, mainly PKC and PKA, that phosphorylate the protein targets involved in axonal disconnection or consolidation and synapse maturation [29,58,59].…”

“…We hypothesize that the relationship between PKA and PKC activities in some nerve endings play a leading role in synapse elimination [29]. The results here show that PKA activity delays both axonal elimination and the differentiation of nicotinic acetylcholine receptor (nAChR) clusters.…”

The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling

“…This includes muscarinic acetylcholine autoreceptors (mAChRs) [31][32][33][34][35], TrkB [36] and adenosine receptors (AR) [37]. Moreover, we widely investigated the functional complex network constituted by these receptors and the presynaptic serine-threonine kinases, PKC and PKA, to regulate ACh release at the NMJ [38]. Furthermore, we presented the individual and complementary actions of presynaptic activity and the resulting muscle contraction over presynaptic kinases, and showed that BDNF/TrkB signaling is key in their regulation [36,39,40], which reveals the mutual intercommunication and regulation between the nerve terminal and the myocyte activities.…”

Myasthenia Gravis: From the Viewpoint of Pathogenicity Focusing on Acetylcholine Receptor Clustering, Trans-Synaptic Homeostasis and Synaptic Stability

“…This may reflect the impairment of the presynaptic Ca 2+ homeostasis for ACh release (Takamori, 2012) to compensate for postsynaptic dysfunction. The presynaptic Ca 2+ homeostasis is promoted by the activation of G protein-coupled receptors such as M1-type muscarinic AChR (M1 mAChR) and A2A adenosine receptor along with the interaction of brain-derived neurotrophic factor (BDNF) with receptor tyrosine kinase B (TrkB); these biological mechanisms lead to P/Q-type VGCC activation by the signaling mediated by phospholipase C (PLC)-phosphatidylinositol 4,5-bisphosphate (PIP2)-diacylglycerol (DAG)-protein kinase C (PKC; Amaral and Pozzo-Miller, 2012;Santafé et al, 2015;Nadal et al, 2016;Hurtado et al, 2017;Simö et al, 2018;Tomàs et al, 2018). Also, PLC-generated DAG regulates the presynaptic vesicle priming protein (Munc13-1) to recruit ACh-containing vesicles for the immediately releasable pool (Bauer et al, 2007).…”