Inhibition of neurotransmitter release

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

As to be expected from a peptide that has been highly conserved during evolution, NPY has many effects, e.g. in the central and peripheral nervous system, in the cardiovascular, metabolic and reproductive system. Central effects include a potent stimulation of food intake and appetite control [2], anxiolytic effects, anti-seizure activity and various forms of neuroendocrine modulation. In the central and peripheral nervous system NPY receptors (mostly Y2 subtype) mediate prejunctional inhibition of neurotransmitter release. In the periphery NPY is a potent direct vasoconstrictor, and it potentiates vasoconstriction by other agents (mostly via Yi receptors) despite reductions of renal blood flow, NPY enhances diuresis and natriuresis. NPY can inhibit pancreatic insulin release and inhibit lipolysis in adipocytes. It also can regulate gut motility and gastrointestinal and renal epithelial secretion. 

Effects Hyperpolarisation of neurons, inhibition of neurotransmitter release ... 

INHIBITION OF NEUROTRANSMITTER RELEASE BY PRESYNAPTIC SEROTONIN HETERORECEPTORS... 

Activation of K+ channels, inactivation of Ca2+ channels and direct inhibition of neurotransmitter release are powerful mechanisms by which opioids inhibit the neuronal transmission of the pain signal. 

Dolly O. Synaptic transmission inhibition of neurotransmitter release by botulinum toxins. Headache. 2003 43(suppl 1) S16-S24. 

Aga IVA and ro-conotoxin GVIA are standard tools in elucidating the roles of P/Q-type and N-type calcium channels in synaptic transmission. In many types of synapses, application of either toxin may mediate moderate inhibition of neurotransmitter release, whereas co-application of both blockers may almost abolish synaptic transmission due to the nonlinear dependence of synaptic release on intracellular calcium concentration. On a final note, we should add that there are many other species of cone snails and spiders that produce active toxins which selectivity inhibit specific calcium channel subtypes (for example, co-conotoxins GVIB, GVIC, GVIIA, SVIA, SVIB), and it is likely that many more remain to be discovered (Olivera et al. 1994). 

Adenosine Receptor-Mediated Inhibition of Neurotransmitter Release.341... 

Inhibition of neurotransmitter release mediated by Ai adenosine receptors is a widespread phenomenon. As mentioned in Section 1, it was first described for cholinergic neurons. But presynaptic Ai receptors also inhibit the release of several other neurotransmitters both in CNS and PNS. Table 2 summarizes early relevant studies. As to postganglionic parasympathetic neurons, there is only one study to our knowledge. In that study, carried out in guinea pig atria, no A] receptor-mediated modulation of acetylcholine release was found (Nakatsuka et al. 1995). 

Table 4 Inhibition of Neurotransmitter Release Through P2 Receptors...

Compelling evidence indicates that a major function of GABAbRs is to mediate inhibition of neurotransmitter release from nerve terminals where they are localized as presynaptic auto- and heteroreceptors (see Bonanno and Raiteri 1993a Bowery et al. 2002 Raiteri 2006, for reviews). 

Cannabinoid and endocannabinoid-induced synaptic depression is observed in both the peripheral nervous system and the CNS. Indeed, A9-THC inhibition of transmitter release was first demonstrated in mouse vas deferens (Graham et al. 1974), and further evidence for presynaptic inhibition has been obtained using this preparation (Ishac et al. 1996 Pertwee and Fernando 1996) and in the myenteric plexus (Coutts and Pertwee 1997 Kulkami-Narla and Brown 2000). In addition, anandamide was first characterized as an EC based on its actions in the mouse vas deferens (Devane et al. 1992). Subsequently, CB1 receptor-mediated inhibition of release of several neurotransmitters has been documented in various regions of the PNS (see Szabo and Schlicker 2005 for review). Cannabinoids also inhibit neural effects on contraction in the ileum (Croci et al. 1998 Lopez-Redondo et al. 1997), although it is not clear that this is effect involves direct inhibition of neurotransmitter release (Croci et al. 1998). The CB1 receptor has been localized to enteric neurons, and thus the effect on ileum certainly involves actions on these presynaptic neurons. In addition, anandamide produces ileal relaxation via a non-CBl, non-CB2-mediated mechanism (Mang et al. 2001). 

G-protein a-subunits, opening of K+ channels, membrane hyperpolarization, and consequent fall of Ca2+ entry that, in turn, decreases glutamate release. Similar mechanisms underlie cannabinoid-mediated inhibition of neurotransmitter release in other brain regions, such as the striatum (Gerdeman and Lovinger, 2001 Huang et ai, 2001), the nucleus accumbens (Robbe et al., 2001) and lateral amygdala (Azad et al., 2003). 

Dual inhibitors also demonstrate other therapeutical benefits. They reduced the coronary vasoconstriction in arthritic hearts in a rat model [101], and significantly decreased angiotensin II-induced contractions in human internal mammary artery [102], Opioid receptor activation can cause a presynaptic inhibition of neurotransmitter release mediated by LOX metabolites of arachidonic acid in midbrain neurons. The efficacy of opioids was enhanced synergistically by treatment of brain neurons with COX and LOX dual inhibitors. This report might lead to development of CNS analgesic medications involving combinations of lowered doses of opioids and COX/LOX dual inhibitors [103]. The COX and 5-LOX dual inhibitors also can prevent lens protein-induced ocular inflammation in both the early and late phases [104]. 

At micromolar concentrations opioids cause an increase in the cell membrane threshold, shortened action potentials, and inhibition of neurotransmitter release. At nanomolar concentrations opioid agonists are excitatory and prolong the action potential via the stimulatory G proteins, which act on the adenylate cyclase/cAMP system and on protein kinase A-dependent ion channels. Tolerance is proposed to be the result of an increase in the association of opioid receptors to stimulatory G proteins, to an activation of A-methyl-o-aspartate receptors via protein kinase C, and calmodulin-dependent increases in cytosolic calcium, resulting in cellular hyperexcitability. 

Link E, Edelmann L, Chou et al. (1992) Tetanus toxin action inhibition of neurotransmitter release linked to synaptobrevin proteolysis. Biochem. Biophys. Res. Comm. 189 1017-23. 

Poulain B, Mochida S, Wadsworth JD et al. (1990) Inhibition of neurotransmitter release by botulinum neurotoxins and tetanus toxin at Aplysia synapses role of the constituent chains. J. Physiol. (Paris) 84 247-61. 

Many nerves are excitatory, however, the binding of neurotransmitters to inhibitory receptors on the postsynaptic membrane causes the opening of and Cf ion chaimels that hyperpolarise the membrane and thus blocks the generation of an action potential. Neuroreceptors are foimd at the post- and presynaptic membrane. Activation of presynaptic receptors usually leads to an inhibition of neurotransmitter release, whereas their inhibition results in an enhanced release of neurotransmitters. 

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