Neuroscience
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The dopaminergic system integrated by cell groups distributed in several brain regions exerts a modulatory role in brain. Particularly important for this task are the mesencephalic dopamine neurons, which from the substantia nigra and ventral tegmental area project to the dorsal striatum and the cortical/subcortical limbic systems, respectively. Dopamine released from these neurons operates mainly via the short distance extrasynaptic volume transmission and activates five different dopaminergic receptor subtypes modulating synaptic GABA and glutamate transmission. ⋯ The aim of this work is to review some novel and conventional approaches that either have been used or are currently employed to treat these diseases. Particular attention is paid to the approaches derived from the knowledge recently acquired in the realm of receptor-receptor interactions taking place through multiple dopamine heteroreceptor complexes in the plasma membrane. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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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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This mini-review starts with a summary of the crucial contributions Ricardo Miledi made to our understanding of how the action potential triggers fast, synchronous transmitter release. It then transitions to the discovery of synaptotagmin and its role as the exocytotic Ca2+ sensor at nerve terminals. The final section confronts the array of unique models that have been proposed to explain the membrane fusion step of exocytosis. ⋯ It will be an interesting challenge for the field to distinguish among these possibilities. Nevertheless, with ongoing technological advances, perhaps we will have a better picture of this process by the end of the coming decade. This article is part of a Special Issue entitled: 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.