Presynaptic Ca2 channels

Catterall WA (1999) Interactions of presynaptic Ca2+ channels and snare proteins in neurotransmitter release. Ann N Y Acad Sci 868 144—159... 

Presynaptic G-protein coupled receptors for a large number of neurotransmitters, both autoreceptors and receptors for extrinsic signals, suppress Ca2+-channel gating in response to an action potential. This mechanism of action appears to be the dominant mechanism involved in short-term plasticity mediated by presynaptic receptors. A typical example is depolarization-induced suppression of inhibition (DSI), which is the short-term suppression of presynaptic GABA-release induced by the depolarization of the postsynaptic cell (Diana and Marty, 2004). DSI is caused when the postsynaptic depolarization causes the release of endocannabinoids from the postsynaptic cell, and the endocannabinoids then bind to presynaptic CB1 receptors whose activation suppresses presynaptic Ca2+-channels. Like many other forms of presynaptic suppression mediated by activation of presynaptic receptors, this effect is short-lasting (in the millisecond range). The precise mechanisms by which Ca2+-channels are suppressed appear to vary between receptors, but the outcome is always a very effective short-term decrease in synaptic signaling. 

Jarvis SE, Zamponi GW (2001a) Distinct molecular determinants govern syntaxin lA-mediated inactivation and G-protein inhibition of N-type calcium channels. J Neurosci 21 2939 18 Jarvis SE, Zamponi GW (2001b) Interactions between presynaptic Ca2+ channels, cytoplasmic messengers and proteins of the synaptic vesicle release complex. Trends Pharmacol Sci 22 519-25... 

Qin N, Platano D, Olcese R, Stefani E, Birnbaumer L (1997) Direct interaction of gbetagamma with a C-terminal gbetagamma-binding domain of the Ca2+ channel alphal subunit is responsible for channel inhibition by G protein-coupled receptors. Proc Natl Acad Sci U S A 94 8866-71 Randall A, Tsien RW (1995) Pharmacological dissection of multiple types of Ca2+ channel currents in rat cerebellar granule neurons. J Neurosci 15 2995-3012 Reid CA, Bekkers JM, Clements JD (2003) Presynaptic Ca2+ channels a functional patchwork. Trends Neurosci 26 683-7... 

Han J, Mark MD, Li X et al (2006) RGS2 determines short-term synaptic plasticity in hippocampal neurons by regulating Gi/o-mediated inhibition of presynaptic Ca2+ channels. Neuron 51 575-86... 

What are the molecular mechanisms of presynaptic NO/cGMP signalling that alter transmitter release In some systems, NO-induced transmitter release occurs independently of an increase in presynaptic Ca2+ (Schuman et al. 1994 Stewart et al. 1996), perhaps by modulating the interaction of components of the vesicle docking/fusion machinery (Meffert et al. 1996). On the other hand, it has been reported that one action of presynaptic cGMP required for LTD induction is the stimulation of presynaptic ryanodine receptor-mediated Ca2+ release (Reyes and Stanton 1996 Reyes-Harde et al. 1999a), but how an increase in presynaptic Ca2+ results in long-term reduction of release probability is not clear. An alternative mechanism to increase Ca2+ is the stimulation of presynaptic Ca2+ channels. In the brain stem, for... 

Reid CA, Bekkers JM, Clements JD (2003) Presynaptic Ca2+ channels a functional patchwork. Trends Neurosci 26 683-7... 

Synaptic Transmission. Figure 1 Synaptic transmission. The presynaptic terminal contains voltage-dependent Na Superscript and Ca2+ channels, vesicles with a vesicular neurotransmitter transporter VNT, a plasmalemmal neurotransmitter transporter PNT, and a presynaptic G protein-coupled receptor GPCR with its G protein and its effector E the inset also shows the vesicular H+ pump. The postsynaptic cell contains two ligand-gated ion channels LGIC, one for Na+ and K+ and one for Cl-, a postsynaptic GPRC, and a PNT. In this synapse, released transmitter is inactivated by uptake into cells. 

G0 was isolated as an other PTx-ribosylated G-protein which co-purifies with G, but which does not inhibit adenylate cyclase. There are two main isoforms (G0l and Go2), with additional splice-variants. G0 is particularly abundant in the nervous system, comprising up to 1% of membrane proteins. Its main function is to reduce the opening probability of those voltage-gated Ca2+ channels (N- and P/Q-type) involved in neurotransmitter release. Hence, it is largely responsible for the widespread auto-inhibition of transmitter secretion by presynaptic receptors and this effect is mediated through released py subunits. 

G -protein-coupled receptors are often located on the presynaptic plasma membrane where they inhibit neurotransmitter release by reducing the opening of Ca2+ channels like inactivation and breakdown of the neurotransmitter by enzymes, this contributes to the neuron s ability to produce a sharply timed signal. An a2 receptor located on the presynaptic membrane of a noradrenaline-containing neuron is called an autoreceptor but, if located on any other type of presynaptic neuronal membrane (e.g., a 5-HT neuron), then it is referred to as a heteroreceptor (Langer, 1997). Autoreceptors are also located on the soma (cell body) and dendrites of the neuron for example, somatodendritic 5-HTia receptors reduce the electrical activity of 5-HT neurons. 

Ionized calcium (Ca2+) is the most common signal transduction element in cells [66], Excitable cells, like neurons, contain voltage-dependent Ca2+ channels, which enable these cells to drastically increase cytosolic calcium levels. Rapid fluctuations in presynaptic... 

Presynaptic events during synaptic transmission are rapid, dynamic and interconnected. The time between Ca2+ influx and exocytosis in the nerve terminal is very short. At the frog NMJ at room temperature, 0.5-1 ms elapses between the depolarization of the nerve terminal and the beginning of the postsynaptic response. In the squid giant synapse, recordings can be made simultaneously in the presynaptic nerve terminal and in the postsynaptic cell. Voltage-sensitive Ca2+ channels open toward the end of the action potential. The time between Ca2+ influx and the postsynaptic response as measured by the postsynaptic membrane potential is 200 ps (Fig. 10-7). However, measurements made with optical methods to record presynaptic events indicate a delay of only 60 ps between Ca2+ influx and the postsynaptic response at 38°C [21]. 

Lambert-Eaton syndrome is an antibody-mediated neuromuscular junction disorder. This disorder, which is most frequently encountered in patients with small-cell lung carcinoma, is characterized clinically by weakness and hyporeflexia. The impaired release of acetylcholine vesicles from presynaptic terminals at neuromuscular junctions that causes the weakness is a consequence of autoantibodies against small cell carcinoma epitopes that cross-react with and downregulate the expression of motor nerve terminal Ca2+ channels [39]. (See in Ch. 43.)... 

Gabapentin Decreases excitatory transmission by acting on VG Ca2+ channels presynaptically(a25 subunit) Bioavailability 50%, decreasing with increasing doses not bound to plasma proteins not metabolized ti/2 6—8 h Generalized tonic-clonic seizures, partial seizures, generalized seizures Toxicity Somnolence, dizziness, ataxia Interactions Minimal... 

As a result of these actions opioids inhibit neurotransmission at the presynaptic and postsynaptic sites. Presynaptic inhibition depends mostly on the direct inhibitory effect on transmitter exocytosis from membrane-associated storage vessels. This direct effect is increased by the inhibition of Ca2+ channels, since Ca2+ ions trigger the transmitter release. Activation of K+ ions induces membrane hyperpolarization which is the most important action component of postsynaptic inhibition. 

N-type Ca2+ channels for instance are located at presynaptic termini of neurons where they are directly involved in the regulation of neurotransmitter release. Staining of the dorsal laminae of the rat spinal cord revealed a complementary distribution of class A and class B Ca2+ channels in nerve terminals in the deeper versus the superficial laminae. Many of the nerve terminals immunoreactive for class B N-type Ca2+ channels also contain substance P, an important neuropeptide in pain pathways, suggesting the N-type Ca2+ channels are predominant at synapses that carry nociceptive information to the spinal cord (Westernbroek etal., 1998). 

The modulation of the N-type Ca2+ channels has been shown for some presynaptic receptors to be the mechanistic basis for the inhibition of Ca2+ influx [29]. In 1989 Takemura et al. [30] reported on the effective inhibition of histamine release from rat hypothalamic slices by the N-type Ca2+ -channel blocker ca-conotoxin. In addition Endou et al. [23] showed that to-conotoxin greatly potentiated the modulatory effect of (R)a-methylhistamine on cardiac adrenergic responses. Yang and Hatton [31] provided direct evidence for an H3 receptor-mediated modulation of ion permeability of neurons. They showed that in magnocellular histaminergic neurons from the rat posterior hypothalamus, H3... 

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