Neuroscience
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Since the pioneering works of Ricardo Miledi, the neuromuscular junction represents the best example of a synapse where ACh is the neurotransmitter acting on nicotinic ACh receptors. ATP, co-released with ACh, is promptly degraded to Ado, which acts as a modulator of the cholinergic synaptic activity. Consequently, both ACh and adenosine play a crucial role in controlling the nerve-muscle communication. ⋯ In this review, we will describe the two systems and their interplay in non-innervated differentiating skeletal muscle cells, and in innervated adult skeletal muscle fibers. We believe that the better comprehension of the interactions between the activity of nAChRs and adenosine could help the knowledge of skeletal muscle physiology. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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Although Ca2+ influx through muscle nAChR-channels has been described over the past 40 years, its functions remain still poorly understood. In this review we suggest possible roles of Ca2+ entry at all stages of muscle development, summarizing the evidence present in literature. nAChRs are expressed in myoblasts prior to fusion, and can be activated in the absence of an ACh-releasing nerve terminal, with Ca2+ influx likely contributing to regulate cell fusion. Upon establishment of nerve-muscle contact, Ca2+ influx contributes to orchestrate the signaling required for the correct formation of the neuromuscular junction. ⋯ However, when genetic defects cause excessive channel activation, Ca2+ influx becomes toxic and causes endplate myopathy. Throughout the review, we highlight how Ricardo Miledi has contributed to construct this whole body of knowledge, from the initial description of Ca2+ permeability of endplate nAChR channels, to the rationale for the treatment of endplate excitotoxic damage under pathological conditions. This article is part of a Special Issue entitled: SI: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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Review
Presynaptic Black Box Opened by Pioneers at Biophysics Department in University College London.
The mechanism of chemical synaptic transmission was elucidated at the frog neuromuscular junction (NMJ) and at the squid giant synapse by Katz, Miledi and other researchers. Later progress in molecular biology revealed numerous types of proteins in mammalian central synapses. To establish molecular-functional correlation in synaptic transmission, it now seems essential to re-address the fundamental mechanisms at mammalian central synapses. ⋯ However, at the calyx of Held, unlike at the squid synapse, the input-output relationship had a wide safety margin, protecting transmitter release from a diminishment of presynaptic action potentials. As in the NMJ, Ca2+ remaining in the cytosol after action potential facilitates subsequent release. As a downstream mechanism of this residual Ca2+, a Ca2+-induced Ca2+ channel activation via high-affinity Ca2+ binding proteins was discovered at mammalian central synapses.
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Myasthenia gravis (MG) is a relatively rare neurological disease that is usually associated with antibodies to the acetylcholine receptor (AChR). These antibodies (Abs) cause loss of the AChRs from the neuromuscular junction (NMJ), resulting in muscle weakness that can be life-threatening. Another form of the disease is caused by antibodies to muscle specific kinase (MuSK) that result in impaired AChR clustering and numbers at the NMJ, and may also interfere with presynaptic adaptive mechanisms. ⋯ All four conditions can be diagnosed by specific clinical features, electromyography and serum antibody tests, and can be treated effectively by a combination of pharmacological approaches and procedures that reduce the levels of the IgG antibodies. They form the first of a spectrum of diseases in which serum autoantibodies bind to extracellular domains of neuronal proteins throughout the nervous system and lead to constellations of clinical features including paralysis, sensory disturbance and pain, memory loss, seizures, psychiatric disturbance and movement disorders. This review will briefly summarize the ways in which this field has developed, since the 1970s when considerable contributions were made in Ricardo Miledi's laboratory at UCL.
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Gambierol is a marine polycyclic ether toxin, first isolated from cultured Gambierdiscus toxicus dinoflagellates collected in French Polynesia. The chemical synthesis of gambierol permitted the analyses of its mode of action which includes the selective inhibition of voltage-gated K+ (KV) channels. In the present study we investigated the action of synthetic gambierol at vertebrate neuromuscular junctions using conventional techniques. ⋯ Results show that nanomolar concentrations of gambierol inhibited the fast K+ current and prolonged the duration of the presynaptic action potential in motor nerve terminals, as revealed by presynaptic focal current recordings, increased stimulus-evoked quantal content in junctions blocked by high Mg2+-low Ca2+ medium, and by BoNT/A, reversed the postsynaptic block produced by d-tubocurarine and increased the transient Ca2+ signals in response to nerve-stimulation (1-10 Hz) in nerve terminals loaded with fluo-3/AM. The results suggest that gambierol, which on equimolar basis is more potent than 3,4-diaminopyridine, can have potential application in pathologies in which it is necessary to antagonize pre- or post-synaptic neuromuscular block, or both. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.