Seminars in Neuroscience最新文献

Long-term potentiation (LTP) and depression (LTD) are considered to be an initial step in processes governing experience-dependent changes in neuronal function in cerebral neocortex. As a mechanism for the induction of LTP and LTD, it is hypothesized that an input-associated rise of Ca²⁺beyond a certain threshold at postsynaptic sites leads to LTP while a lower rise below the threshold leads to LTD. To test this Ca²⁺-switching hypothesis, the method of microscopic fluorometry with Ca²⁺indicators such as fura-2 has been employed. In this review, problems with this fura-2 method are described, and results obtained with other indicators having weaker Ca²⁺-chelating action are mentioned briefly. Experimental results indicating the involvement of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase (calcineurin) are also reviewed, and a model that includes the spatiotemporal dynamics of Ca²⁺and the intracellular location of both enzymes as variables is proposed as a modification of the Ca²⁺-switching hypothesis.

Cerebellar Purkinje neurones display two forms of synaptic plasticity that critically depend on a transient increase in intracellular Ca²⁺for their induction. They are a long-term depression (LTD) of the excitatory glutamatergic parallel fibre input, and a long-lasting potentiation, called rebound potentiation (RP), of inhibitory inputs mediated by γ-aminobutyric acid. A number of mechanisms could participate in the increase in cytoplasmic Ca²⁺concentration. These include Ca²⁺entry from the extracellular space through voltage-gated Ca²⁺channels and ionotropic glutamate receptors, and Ca²⁺release from intracellular stores sensitive to Ca²⁺and inositol trisphosphate. The evidence obtained from cerebellar slices suggests that, of these, the activation of P-type voltage-gated Ca²⁺channels by membrane depolarization provides the predominant amount of Ca²⁺necessary for the induction of LTD and RP.

Excitatory neurotransmission is mainly mediated by cationic channels activated by glutamate in the mammalian central nervous system (CNS). Molecular cloning and expression studies have revealed that the subtype diversity of the glutamate receptor channel is much larger than expected from pharmacological studies. Among various types of glutamate receptor channels, the NMDA receptor channel is most permeable to Ca²⁺. The Ca²⁺permeability of the AMPA receptor channel depends on the subunit composition. The receptor channel lacking the edited form of GluR2 subunit has a substantial permeability to Ca²⁺. Physiological and pathological implications of the Ca²⁺inflow through these glutamate receptor channels are discussed.

Extracellular purines play multiple roles in a variety of sensory systems acting as neural signalling and humoral factors via purinoceptors. For example, ATP and adenosine have a neurosignalling role in autonomic sensory–motor reflexes, mechanoreception and chemoreception mediated via vagus nerve afferents, and in nociception. Purinergic neuromodulation of vision via adenosine in the retina is well established and there is mounting evidence for a neuromodulatory role for ATP in the inner ear. Humoral purinergic actions are found in the eye where adenosine clearly has an important vascular and humoral influence and in the inner ear where ATP probably regulates fluid homeostasis, hearing sensitivity and development. Clearly purinergic signalling underpins the physiology of many of the body's sensory systems.

Six P2X receptor subunits are currently known, encoded on different genes. The proteins deduced from their cDNAs have 379 to 472 amino acids; they are 36–48% identical. They are thought to have two transmembrane segments, with most of the protein forming a large extracellular loop. In-situ hybridization shows a widespread tissue distribution of the RNAs, with P2X₄and P2X₆being the receptors most heavily expressed in brain and P2X₃found only in sensory ganglia. P2X₁–P2X₄subunits readily form channels when expressed in mammalian cells or oocytes; the number of subunits per channel is not known, although P2X₂and P2X₃can both contribute to the same channel when co-expressed. P2X₅and P2X₆express less readily, suggesting perhaps that they normally co-assemble with other subunits. Experiments in progress seek to determine the stoichiometry of the P2X receptor channel and the parts of the molecule involved in pore formation and ATP binding.

During the past decade it has become clear that cotransmission is the rule rather than the exception in the autonomic nervous system. The role of ATP as a cotransmitter has been most extensively investigated in sympathetic nerves innervating smooth muscle preparations such as isolated vas deferens and arteries.

This article describes how the role of ATP as a sympathetic cotransmitter has been established by a combination of various experimental methods including classical organ bath pharmacology, electrophysiology and a variety of biochemical methods for measuring neurotransmitter release.

The urinary bladder and the small intestine are presented as the principal models of purinergic cotransmission in the parasympathetic and enteric nervous systems, drawing upon evidence provided by functional, histochemical and ultrastructural studies. In the parasympathetic division ATP probably commonly transmits alongside acetylcholine, and in enteric nerves it is more likely to be transmitting alongside nitric oxide and VIP. Other organs, including some blood vessels and exocrine glands, in which there are hints that ATP might be involved as a parasympathetic cotransmitter are also given consideration.

No abstract.

The role of ecto-ATPase in modulating the purinergic component of neurotransmission in the guinea-pig vas deferens has been investigated using ARL 67156, a recently developed inhibitor of ecto-ATPase. ARL 67156 rapidly and reversibly potentiated neurogenic contractions in a concentration-dependent manner. ARL 67156 also potentiated contractions evoked by exogenous ATP, but had no effect on those to the stable analogue α,β-methyleneATP or on those to noradrenaline and KCl in the presence of the P₂-purinoceptor antagonist PPADS. These results are consistent with an inhibitory action of ARL 67156 on ecto-ATPase and suggest that ecto-ATPase modulates purinergic neurotransmission in the guinea-pig vas deferens.

Adenosine 5′-triphosphate (ATP) is a ubiquitous substance in the central and peripheral nervous system. Nerve terminal ATP is generated from ADP, during glycolysis, citric acid cycle and predominantly by oxidative phosphorylation in the mitochondria. The adenine ring is synthesized via de-novo purine biosynthesis, and also by purine salvage pathways. The main regulator of ATP synthesis is ADP, the signal of the actual energy state of the neuron. It inhibits (negative feedback) its own synthesis and also regulates mitochondrial oxidative phosphorylation.

Storage of ATP has been shown in all types of synaptic vesicles and it can also be found in the cytoplasm in millimolar range. ATP can be co-packaged with other neurotransmitters such as acetylcholine and noradrenaline and may be stored in purinergic vesicles and, perhaps, in purinergic nerve endings. Various treatments can alter vesicular composition, and hence, vesicular neurotransmitter/ATP ratio.

There is now wide acceptance that ATP is released stimulation-dependently from nerve endings of a number of isolated tissues and preparations upon depolarizing stimuli. In addition to presynaptically derived ATP, ATP release from activated target cells in response to the action of primary transmitter on postsynaptic receptors also forms a significant contribution to neuronal outflow in several tissues. As for the possible role of intraterminal ATP pools in the release process, recent observations support the view that ATP is released as a genuine cotransmitter, or as a principal purinergic neurotransmitter in an exocytotic way, but also indicate the involvement of other neuronal pools of ATP in the release, such as carrier-mediated release from the cytoplasm.