Suppression of charge movement by calcium antagonists is not related to calcium channel block

The calcium channel-inhibiting drugs nitrendipine and diltiazem represent two important classes of organic calcium antagonists. In the present study, the effect of these drugs on calcium currents and charge displacement currents in bullfrog semitendinosus muscle fibers was examined using a vaseline gap voltage clamp. Nitrendipine (10 M) reduced the quantity of charge that moved both during the ON phase (Q_ON) and the OFF phase (Q_OFF) of charge movement. This action appeared to be most selective for Q_ON. However, at this same concentration, nitrendipine had no blocking action on inward calcium currents. In contrast to these findings, diltiazem blocked calcium currents in a concentration-dependent manner, while slightly increasing the quantity of charge moved during Q_ON and Q_OFF. The enhancement of charge movement by diltiazem resulted from two actions. First, diltiazem shifted the voltage-dependence of charge movement to more negative potentials. Second, diltiazem increased the maximum amount of charge moved. (Supported by NIH NS 03178 and HL 07382.)     

Effect of N-phthalamoyl-L-glutamic acid,a selective NMDA receptor agonist,on binding of3H-L-glutamate with hippocampal synaptic membranes

Institute of Experimental Medicine, Russian Academy of Medical Sciences, St. Petersburg. (Presented by Academician of the Russian Academy of Medical Sciences A. N. Klimov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 113, No. 6, pp. 563–565, June, 1992.     

Differential sensitivity of selected rat brain areas to excitatory neurotransmitters released by K+ depolarization

When injected intrathecally in mice in a volume of 5 microliter, adenosine had no effect on tail-flick or hot-plate reaction latencies at dosages up to 1 mM concentration. There were no other behavioral effects observed either. Injecting 1 mM of the adenosine receptor agonist, 5'-N-ethylcarboxamide adenosine (NECA) caused both motor paralysis of the hind-legs with a duration of approximately 4 h and simultaneous antinociception. A slight weakness of the hindlegs, but a profound antinociceptive effect, was observed after the 100 microM dose only. After 10 microM, there was no effect on motor behavior but still a prolongation of the tail-flick and hot-plate reaction latencies. Pretreatment with the adenosine receptor antagonist theophylline attenuated the antinociceptive effect of NECA. Activation of spinal adenosine receptors thus appears to selectively elicit analgesia.     

Types of nerves in the enteric nervous system

The enteric nervous system is one of the three divisions of the autonomic nervous system, the others being the sympathetic and parasympathetic. In contrast to the other divisions, it can perform many functions independently of the central nervous system. It consists of ganglionated plexuses, their connections with each other, and nerve fibres which arise from the plexuses and supply the muscle, blood vessels and mucosa of the gastrointestinal tract. The enteric nervous system contains a large number of neurons, approximately 10⁷ to 10⁸. About ten or more distinct types of enteric neurons have been distinguished on electrical, pharmacological, histochemical, biochemical and ultrastructural grounds as well as on the basis of their modes of action. Both excitatory and inhibitory nerves supply the muscle and there are inhibitory and excitatory interneurons within the enteric plexuses. There are also enteric nerves which supply intestinal glands and blood vessels, but these receive less emphasis in this commentary.Correlations between groups of neurons defined on different criteria are poor and in many cases the physiological roles of the nerves are not known. The functions of noradrenergic nerves which are of extrinsic origin are reasonably well understood, but cholinergic nerves in the intestine are the only intrinsic nerves for which both the transmitter and to some extent the functions are known. In the case of non-cholinergic, non-noradrenergic enteric inhibitory nerves, the functions are understood but the transmitter is yet to be determined, both adenosine 5′-triphosphate and vasoactive intestinal polypeptide having been proposed. Other nerves have been defined pharmacologically (non-cholinergic excitatory nerves to neurons and muscle, intrinsic inhibitory inputs to neurons, and enteric, non-cholinergic vasodilator nerves) and histochemically (intrinsic amine-handling neurons and separate neurons containing peptides: substance P, somatostatin, enkephalins, vasoactive intestinal polypeptide, gastrin cholecystokinin tetrapeptide, bombesin, neurotensin and probably other peptides). Little is known of the functions of these nerves, although a number of proposals which have been made are discussed.     

Photoreception and sensory transduction in Aneural Organisms,NATO advanced study institutes series A,Vol. 33: Edited by Francesco Lenci and Giuliano Colombetti Plenum Press,New York, 1980. $45.00 in U.S.A. and Canada and $54.00 outside U.S.A. and Canada (432 pp.) ISBN 0-306-404370-0

(?) 2-Amino-7-phosphonoheptanoate and (?) 2-amino-5-phosphonovalerate were shown to possess selective and powerful antagonistic activity vis-à-vis the neurotoxic effects of ibotenic acid in the rat hippocampal formation. The neurotoxicity of kainic acid was not blocked by either drug.     

Decay kinetics of calcium currents in rat sensory neurones: analysis at two internal free calcium concentrations

The patch-clamp technique in whole-cell configuration was, used to investigate the kinetics of decay of calcium currents in rat sensory neurones. Whole-cell recording permitted control of the internal medium, particularly of the internal free calcium concentration, which was maintained at either 10^–9 M or 10^–6 M using a high concentration of Ca buffer. The inactivation decay of the total Ca current elicited above –10 mV was found to be faster at pCa 6 than at pCa 9. The total current contained three exponential components which were tentatively identified as the three types of Ca currents (ICa_T, ICa_N and ICa_S). Kinetic analyses indicated that the control of the inactivation process by internal Ca results from an effect on both high-threshold Ca currents, ICa_N, and ICa_S. The inactivation kinetics reported in the literature presents a large variability depending on the cell type. We propose that this variability may result from differences in the capacity of those cells to control their internal Ca.     

The actin binding domain of ACF7 binds directly to the tetratricopeptide repeat domains of rapsyn

Formation of the neuromuscular junction requires the release of agrin from the presynaptic terminal of motor neurons. Clustering of acetylcholine receptors (AChRs) on the postsynaptic sarcolemma is initiated by agrin-dependent activation of the muscle-specific kinase. While the postsynaptic scaffolding protein rapsyn is vital for high density AChR aggregation, little is known about the mechanism through which AChRs are immobilized on the postsynaptic membrane. Ultrastructural and immunohistochemical studies of rat skeletal muscle have suggested that AChRs are anchored to a membrane-associated cytoskeleton that contains spectrin-like proteins and is thus similar to that of the human erythrocyte [Bloch RJ, Bezakova G, Ursitti JA, Zhou D, Pumplin DW (1997) A membrane skeleton that clusters nicotinic acetylcholine receptors in muscle. Soc Gen Physiol Ser 52:177–195]. We are studying a protein of the spectrin superfamily, ACF7 (also known as MACF), as a postsynaptic cytoskeletal component of the neuromuscular junction. ACF7 has multiple cytoskeleton-binding domains, including an N-terminal actin-binding domain that, we postulate, may interact with rapsyn, the scaffolding protein that binds directly to AChRs. To test this hypothesis, we co-expressed fragments of these molecules in cultured fibroblasts and assessed their co-distribution and interaction using confocal microscopy and co-immunoprecipitation. We demonstrate that the actin-binding domain of ACF7 specifically interacts with the tetratricopeptide repeat domains of rapsyn. Furthermore, we show using surface plasmon resonance and blot overlay that the actin-binding domain of ACF7 binds directly to rapsyn. These results suggest that, in mammalian skeletal muscle, AChRs are immobilized in the membrane through rapsyn-mediated anchoring to an ACF7-containing network that in turn is linked to the actin cytoskeleton.     

Frequency dependence of the cardiac threshold to alternating current between 10 Hz and 160 Hz

It is still unclear what fundamental criteria influence the ability of alternating current (AC) to induce ventricular fibrillation (VF) in vivo. As the VF threshold has a bowl-shaped relationship with frequency (showing a minimum threshold at some frequency), similar to the nervous system, one proposed model has assumed that the mechanisms underlying AC stimulation of nerves are at work for VF induction. More recent work has suggested a second approach, whereby a simple RC-like model is sufficient to understand the cardiac AC stimulation threshold's frequency dependence, suggesting that some unarticulated mechanism is at work for VF. The paper directly tests these two models. In 12 intact dogs and 20 intact guinea pigs, DC pulses were used to stimulate AC square and AC sine waves at 10, 20, 40, 80 and 160 Hz. All electrodes were endocardial, with the return electrode being on a paw or thorax. It was found that, for square and sine wave stimulation in both dogs and guinea pigs, the stimulation threshold increased monotonically with frequency from 10 Hz up to 160 Hz (p<0.01 for dogs and guinea pigs). Between 80 and 160 Hz, the AC stimulation threshold doubled, exactly as predicted by an RC model. It was concluded that the AC stimulation threshold is not bowl-shaped and is best understood with an RC model. As the VF threshold does exhibit a bowl-shape with frequency, as opposed to the stimulation threshold which does not, the VF induction frequency dependence must have different origins.