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Journal ArticleDOI

Further study of the role of calcium in synaptic transmission

01 May 1970-The Journal of Physiology (J Physiol)-Vol. 207, Iss: 3, pp 789-801
TL;DR: The effect of calcium on synaptic transmission has been studied by intracellular recording of pre‐ and post‐synaptic potential changes in the stellate ganglion of the squid by using Na6(CO3)(SO4)2, Na2SO4, and Na2CO3 as slurs.
Abstract: 1. The effect of calcium on synaptic transmission has been studied by intracellular recording of pre- and post-synaptic potential changes in the stellate ganglion of the squid.2. For a given presynaptic ;input' (propagated spike, or local depolarizing pulse after tetrodotoxin treatment), the post-synaptic response increases with external calcium concentration [Ca](o) in a highly non-linear fashion, indicating that transmitter output varies with more than the second power of [Ca](o) over a certain concentration range.
Citations
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Journal ArticleDOI
TL;DR: The evidence for this hypothesis, and the origins of the different kinetic phases of synaptic enhancement, as well as the interpretation of statistical changes in transmitter release and roles played by other factors such as alterations in presynaptic Ca(2+) influx or postsynaptic levels of [Ca(2+)]i are discussed.
Abstract: ▪ Abstract Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca2+]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases...

4,687 citations

Journal ArticleDOI
TL;DR: In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial.
Abstract: The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+ in parallel with the PM ATP-driven Ca2+ pump. As a reversible transporter, it also mediates Ca2+ entry in parallel with various ion channels. The energy for net Ca2+ transport by the Na+/Ca2+ exchanger and its direction depend on the Na+, Ca2+, and K+ gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+ are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+ is transported in the same direction as Ca2+, with a coupling ratio of four Na+ to one Ca2+ plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+ exchanger family (NCX1, NCX2, and NCX3) and two in the Na+/Ca2+ plus K+ family (NCKX1 and NCKX2). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila. In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+ concentration lead to increases in Ca2+ concentration mediated by the Na+/Ca2+ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+ and Ca2+ apparently modulate basolateral K+ conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+ exchanger to regulate sarco(endo)plasmic reticulum Ca2+ stores and influence cellular Ca2+ signaling.

1,715 citations

Journal ArticleDOI
TL;DR: Evidence at synapses suggests that inhibition of presynaptic voltage-dependent Ca2+ channels plays the major role inPresynaptic inhibition of elicited neurotransmitter release, and modulation of the release machinery might contribute to inhibition of elicit release.

617 citations

References
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Journal ArticleDOI
TL;DR: The quantitative dependence of transmitter release on external calcium concentration has been studied at the frog neuromuscular junction, using intracellular recording and taking the amplitude of the end‐plate potential (e.p.p.) as an index of the number of packets released.
Abstract: 1. The quantitative dependence of transmitter release on external calcium concentration has been studied at the frog neuromuscular junction, using intracellular recording and taking the amplitude of the end-plate potential (e.p.p.) as an index of the number of packets released. 2. The relation between [Ca] and the e.p.p. is highly non-linear. The initial part of this relation on double logarithmic co-ordinates gives a straight line with a slope of nearly four (mean 3·78 ± 0·2 S.D. in 28 experiments). Addition of a constant amount of Mg reduces the e.p.p. without altering the slope of the log e.p.p./log Ca relation. 3. The slope of this logarithmic relation diminishes as [Ca] is raised towards the normal level. 4. The results are explained quantitatively on the hypothesis that Ca ions combine with a specific site X on the nerve terminal forming CaX, and that the number of packets of acetylcholine released is proportional to the fourth power of [CaX]. 5. The analysis suggests that a co-operative action of about four calcium ions is necessary for the release of each quantal packet of transmitter by the nerve impulse.

1,277 citations

Journal ArticleDOI
TL;DR: The axo‐axonic giant synapse in the stellate ganglion of the squid has been used to study synaptic transmission and provides new insights into the role of Tournaisian reprograming in synaptic transmission.
Abstract: 1. The axo-axonic giant synapse in the stellate ganglion of the squid has been used to study synaptic transmission. 2. When nerve impulses have been eliminated with tetrodotoxin, synaptic transfer of potential changes can still be obtained by applying brief depolarizing pulses to the presynaptic terminal. 3. Suitably matched pulses are as effective as the normal presynaptic spike in evoking post-synaptic potentials. The synaptic delay and the time course of the post-synaptic potential are very similar to that in the normal preparation. 4. The synaptic transfer (input/output) characteristic has been studied under different experimental conditions. With brief (1-2 msec) current pulses, post-synaptic response becomes detectable when the presynaptic depolarization exceeds about 30 mV. The post-synaptic potential increases about tenfold with 10 mV increments of presynaptic depolarization. 5. Calcium increases, magnesium reduces the slope of the synaptic transfer curve. The influences on this curve of (i) duration of the pulse, (ii) preceding level of membrane potential, (iii) position of recording electrode, (iv) rate of repetitive stimulation are described. 6. After loading the synaptic terminal with tetraethylammonium ions, large inside-positive potentials can be produced in the terminal and maintained for many milliseconds. 7. By raising the internal potential to a sufficiently high level, synaptic transfer becomes suppressed during the pulse, and the post-synaptic response is delayed until the end of the pulse. 8. This observation is in accord with a prediction of the ‘calcium hypothesis’, viz. that inward movement of a positively charged Ca compound, or of the calcium ion itself, constitutes one of the essential links in the ‘electro-secretory’ coupling process of the axon terminal.

851 citations

Journal ArticleDOI
TL;DR: The electric properties of the giant synapse in the stellate ganglion of the squid have been further investigated and it is shown that the synapse has an electric property similar to that of a ‘spatially aggregating cell’.
Abstract: 1. The electric properties of the giant synapse in the stellate ganglion of the squid have been further investigated.2. During tetrodotoxin (TTX) paralysis, a local response can be elicited from the terminal parts of the presynaptic axons after intracellular injection of tetraethyl ammonium ions (TEA).3. The response is characterized by an action potential of variable size and duration, whose fall is often preceded by a prolonged plateau. The response, especially the duration of the plateau, is subject to ;fatigue' during repetitive stimulation.4. The TTX-resistant form of activity is localized in the region of the synaptic contacts, and shows a marked electrotonic decrement even within less than 1 mm from the synapse. It is found only on the afferent, not on the efferent, side of the synapse.5. During the plateau of the response, the membrane resistance is greatly reduced below its resting value.6. The response depends on presence of external calcium and increases in size and duration with the calcium concentration. Strontium and barium substitute effectively for calcium. Manganese and, to a lesser extent, magnesium, counteract calcium and reduce the response. The response also declines, and ultimately disappears, if sodium is withdrawn for long periods.7. The relation of the local TTX-resistant response to the influx of calcium ions and to the release of the synaptic transmitter is discussed.

597 citations

Journal ArticleDOI
TL;DR: End-plate potentials in curarized frog muscle have been measured over a range of Ca and Mg concentrations, and the results have been compared with the predictions of this hypothesis to show that the output of ACh should depend on the proportion of the total concentration of X which is combined with calcium.
Abstract: Calcium and magnesium ions are known to have specific and opposite effects at the prejunctional nerve terminals of several cholinergic synapses. A nerve impulse releases more acetylcholine (ACh) if the concentration of Ca is raised, within limits, or if that of Mg is lowered (del Castillo & Stark, 1952; del Castillo & Engbaek, 1954; Hutter & Kostial, 1954). del Castillo & Katz (1954 a, b) have discussed this antagonism and have put forward tentatively the hypothesis that Ca and Mg compete for some site or carrier molecule, X, in the nerve endings: on the arrival of an impulse, the calcium compound alone breaks down to give Ca and an active form of X, X', which can release or allow the passage of ACh. Thus the output of ACh should depend on the proportion of the total concentration of X which is combined with calcium. In the present experiments, end-plate potentials (e.p.p.'s) in curarized frog muscle have been measured over a range of Ca and Mg concentrations, and the results have been compared with the predictions of this hypothesis.

319 citations