Presynaptic calcium channels: pharmacology and regulation (original) (raw)
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Proceedings of the National Academy of Sciences, 1992
We have studied the effect of the purified toxin from the funnel-web spider venom (FTX) and its synthetic analog (sFTX) on transmitter release and presynaptic currents at the mouse neuromuscular junction. FTX specifically blocks the a-conotoxinand dihydropyridine-insensitive P-type voltage-dependent Ca2+ channd (VDCC) in cerebellar Purkinje cells. Mammalian neuromuscular transmission, which is insensitive to N-or L-type Ca2+ channel blockers, was effectively abolished by FTX and sFTX. These substances blocked the muscle contraction and the neurotransmitter release evoked by nerve stimulation. Moreover, presynaptic Ca2+ currents recorded extracellularly from the interior of the perineural sheaths of nerves innervating the mouse levator auris muscle were specifically blocked by both natural toxin and synthetic analogue. In a parallel set of experiments, K+-induced Ca'5 uptake by brain synaptosomes was also shown to be blocked or greatly diminished by FIX and sFVX. These results indicate that the predominant VDCC in the motor nerve terminals, and possibly in a significant percentage of brain synapses, is the P-type channel.
Functional Specialization of Presynaptic Cav2.3 Ca2+ Channels
Neuron, 2003
Epileptology beit with a lower efficacy than N-and P/Q-type Ca 2ϩ channels . University Bonn Sigmund-Freud Str. 25 In addition to fast neurotransmitter release, some forms of synaptic plasticity also require a rise in presyn-53105 Bonn Germany aptic Ca 2ϩ . At the mossy fiber-CA3 synapse, for instance, the induction of synaptic long-term potentiation 3 Department of Neurophysiology University of Cologne (LTP) appears to be independent of Ca 2ϩ influx into the postsynaptic CA3 neurons (Zalutsky and ). Robert-Koch-Str. 39 50931 Kö ln Rather, a rise in presynaptic Ca 2ϩ is thought to be the initial step in LTP induction (Castillo et al., 1994), which Germany subsequently leads to expression of mossy fiber LTP via an increase in the probability of neurotransmitter release (Zalutsky and Nicoll, 1990; Castillo et al., 2002; Maeda et al., 1997; Xiang et al., 1994; but see Yeckel et Summary al. , 1999). The finding that both fast neurotransmitter release and the induction of mossy fiber LTP require a Ca 2؉ influx into presynaptic terminals via voltagedependent Ca 2؉ channels triggers fast neurotransmitter rise in the presynaptic Ca 2ϩ concentration raises the basic question whether both of these processes are release as well as different forms of synaptic plasticity. Using electrophysiological and genetic techniques triggered by Ca 2ϩ entry via identical Ca 2ϩ channel subtypes. In contrast to the detailed knowledge of Ca 2ϩ we demonstrate that presynaptic Ca 2؉ entry through Ca v 2.3 subunits contributes to the induction of mossy channels mediating fast neurotransmitter release at central synapses (Iwasaki and Takahashi, 1998; Qian and fiber LTP and posttetanic potentiation by brief trains of presynaptic action potentials while they do not play a role in fast synaptic transmission, paired-pulse facilitation, or frequency facilitation. This functional spe-it has remained unclear which Ca 2ϩ entry pathways are a factor in presynaptic forms of LTP. Mossy fiber LTP cialization is most likely achieved by a localization remote from the release machinery and by a Ca v 2.3 can be induced when either N-type or P/Q-type Ca 2ϩ channels are blocked (Castillo et al., 1994), and these channel-dependent facilitation of presynaptic Ca 2؉ influx. Thus, the presence of Ca v 2.3 channels boosts the experiments indicate that-aside from N-and P/Q-type Ca 2ϩ channels-additional sources of Ca 2ϩ entry could accumulation of presynaptic Ca 2؉ triggering presynaptic LTP and posttetanic potentiation without affecting contribute to the induction of LTP. R-type Ca 2ϩ channels resistant to organic Ca 2ϩ chan-the low release probability that is a prerequisite for the enormous plasticity displayed by mossy fiber syn-nel antagonists are present at certain presynaptic terminals and may contribute to intraterminal Ca 2ϩ increases apses.
Neuroscience research, 2018
At the presynaptic terminal, neuronal firing activity induces membrane depolarization and subsequent Ca entry through voltage-gated Ca (Ca) channels triggers neurotransmitter release from the active zone. Presynaptic Ca channels form a large signaling complex, which targets synaptic vesicles to Ca channels for efficient release and mediates Ca channel regulation. The presynaptic Ca2 channel family (comprising Ca2.1, Ca2.2 and Ca2.3 isoforms) encode the pore-forming α1 subunit. The cytoplasmic regions are the target of regulatory proteins for channel modulation. Modulation of presynaptic Ca channels has a powerful influence on synaptic transmission. This article overviews spatial and temporal regulation of Ca channels by effectors and sensors of Ca signaling, and describes the emerging evidence for a critical role of Ca channel regulation in control of synaptic transmission and presynaptic plasticity. Sympathetic superior cervical ganglion neurons in culture expressing Ca2.2 channels...
The Journal of Physiology, 2007
P/Q-type and N-type calcium channels mediate transmitter release at rapidly transmitting central synapses, but the reasons for the specific expression of one or the other in each particular synapse are not known. Using whole-cell patch clamping from in vitro slices of the auditory brainstem we have examined presynaptic calcium currents (I pCa ) and glutamatergic excitatory postsynaptic currents (EPSCs) at the calyx of Held synapse from transgenic mice in which the α 1A pore-forming subunit of the P/Q-type Ca 2+ channels is ablated (KO). The power relationship between Ca 2+ influx and quantal output was studied by varying the number of Ca 2+ channels engaged in triggering release. Our results have shown that more overlapping Ca 2+ channel domains are required to trigger exocytosis when N-type replace P/Q-type calcium channels suggesting that P/Q type Ca 2+ channels are more tightly coupled to synaptic vesicles than N-type channels, a hypothesis that is verified by the decrease in EPSC amplitudes in KO synapses when the slow Ca 2+ buffer EGTA-AM was introduced into presynaptic calyces.
Journal of Neurochemistry, 2002
Abstract: The voltage-dependent calcium channels present in mammalian and chicken brain synaptosomes were characterized pharmacologically using specific blockers of L-type channels (1,4-dihydropyridines), N-type channels (ω-conotoxin GVIA), and P-type channels [funnel web toxin (FTX) and ω-agatoxin IVA]. K+-induced Ca2+ uptake by chicken synaptosomes was blocked by ω-conotoxin GVIA (IC50 = 250 nM). This toxin at 5 µM did not block Ca2+ entry into rat frontal cortex synaptosomes. FTX and ω-agatoxin IVA blocked Ca2+ uptake by rat synaptosomes (IC50 = 0.17 µl/ml and 40 nM, respectively). Likewise, in chicken synaptosomes, FTX and ω-agatoxin IVA affected Ca2+ uptake. FTX (3 µl/ml) exerted a maximal inhibition of 40% with an IC50 similar to the one obtained in rat preparations, whereas with ω-agatoxin IVA saturation was not reached even at 5 µM. In chicken preparations, the combined effect of saturating concentrations of FTX (1 µl/ml) and different concentrations of ω-conotoxin GVIA showed no additive effects. However, the effect of saturating concentrations of FTX and ω-conotoxin GVIA was never greater than the one observed with ω-conotoxin GVIA. We also found that 60% of the Ca2+ uptake by rat and chicken synaptosomes was inhibited by ω-conotoxin MVIID (1 µM), a toxin that has a high index of discrimination against N-type channels. Conversely, nitrendipine (10 µM) had no significant effect on Ca2+ uptake in either the rat or the chicken. In conclusion, Ca2+ uptake by rat synaptosomes is potently inhibited by different P-type Ca2+ channel blockers, thus indicating that P-type channels are predominant in this preparation. In contrast, Ca2+ uptake by chicken synaptosomes is sensitive to ω-conotoxin GVIA, FTX, ω-agatoxin IVA, and ω-conotoxin MVIID. This suggests that a channel subtype with a mixed pharmacology is present in chicken synaptosomes.
Calcium-induced modulation of synaptic transmission
Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology, 2007
Calcium (Ca 2+ ) is a second messenger regulating a wide variety of intracellular processes. Using GABA-and glycinergic synapses as examples, this review analyzes two functions of this unique ion: postsynaptic Ca 2+ -dependent modulation of receptor-operated channels and Ca 2+ -induced retrograde regulation of neurotransmitter release from the presynaptic terminals. Phosphorylation, rapid Ca 2+ -induced modulation via intermediate Ca 2+ -binding proteins, and changes in the number of functional receptors represent the main pathways of short-and long-term plasticity of postsynaptic receptor-operated channel machinery. Retrograde signaling is an example of synaptic modulation triggered by stimulation of postsynaptic cells and mediated via regulation of presynaptic neurotransmitter release. This mechanism provides postsynaptic neurons with efficient tools to control the presynaptic afferents in an activity-dependent mode. Elevation of intracellular Ca 2+ in a postsynaptic neuron triggers the synthesis of endocannabinoids (derivatives of arachidonic acid). Their retrograde diffusion through the synaptic cleft and consequent activation of presynaptic G-protein coupled to CB1 receptors inhibits the release of neurotransmitter. These mechanisms of double modulation, which include control over the function of postsynaptic ion channels and retrograde suppression of the release machinery, play an important role in Ca 2+ -dependent control of the main excitatory and inhibitory synaptic pathways in the mammalian nervous system.