Presynaptic modulation of transmitter release

Wonnacott S, Irons J, Rapier C, et al Presynaptic modulation of transmitter release by nicotinic receptors, in Progress in Brain Research. Edited by Nordberg A, Fuxe K, Hohnstedt B, et al. Amsterdam, Elsevier, 1990, pp 157-163... 

Table 1 Presynaptic autoreceptors. Shown are the transmitters for which a negative or positive feedback mechanism mediated by presynaptic autoreceptors has been established. Note that in each case a specific receptor subtype is involved in the presynaptic modulation of transmitter release...

ACh regulates the cortical arousal characteristic of both REM sleep and wakefulness (Semba, 1991, 2000 Sarter Bruno, 1997, 2000). Medial regions of the pontine reticular formation (Figs. 5.2 and 5.7) contribute to regulating both the state of REM sleep and the trait of EEG activation. Within the medial pontine reticular formation, presynaptic cholinergic terminals (Fig. 5.1) that release ACh also are endowed with muscarinic cholinergic receptors (Roth et al, 1996). Autoreceptors are defined as presynaptic receptors that bind the neurotransmitter that is released from the presynaptic terminal (Kalsner, 1990). Autoreceptors provide feedback modulation of transmitter release. Autoreceptor activation... 

Schlicker, E. and Kathmann, M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol. Sci. 22 565-572, 2001. 

Physiological studies have identified both post- and presynaptic roles for ionotropic kainate receptors. Kainate receptors contribute to excitatory post-synaptic currents in many regions of the CNS including hippocampus, cortex, spinal cord and retina. In some cases, postsynaptic kainate receptors are codistributed with AMPA and NMDA receptors, but there are also synapses where transmission is mediated exclusively by postsynaptic kainate receptors for example, in the retina at connections made by cones onto off bipolar cells. Extrasynaptically located postsynaptic kainate receptors are most likely activated by spill-over glutamate (Eder et al. 2003). Modulation of transmitter release by presynaptic kainate receptors can occur at both excitatory and inhibitory synapses. The depolarization of nerve terminals by current flow through ionotropic kainate receptors appears sufficient to account for most examples of presynaptic regulation however, a number of studies have provided evidence for metabotropic effects on transmitter release that can be initiated by activation of kainate receptors. The hyperexcitability evoked by locally applied kainate, which is quite effectively reduced by endocannabinoids, is probably mediated preferentially via an activation of postsynaptic kainate receptors (Marsicano et al. 2003). 

Receptor-dependent vasodilation may also take place in a more indirect manner through the presynaptic modulation of the release of neurotransmitters, such as norepinephrine and acetylcholine. In addition to its effects on postsynaptic receptors, norepinephrine stimulates the presynaptic a2-receptor, thereby inhibiting further transmitter release. Moreover, the activation of other presynaptic receptors such as the muscarinic cholinergic, dopaminergic, purinergic, serotoninergic, and histaminergic receptors leads to diminished norepinephrine release and subsequent vasodilation. 

Ronken E, Mulder AH, Schoffelmeer ANM (1993) Chronic activation of mu and kappa-opioid receptors in cultured catecholaminergic neurons from rat brain causes neuronal supersensitivity without receptor desensitization. J Pharmacol Exp Ther 268 595-9 Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22 565-572... 

Mechanism of action Opioids exert their major effects by interacting with opioid receptors in the CNS and the gastrointestinal tract. Opioids cause hyperpolarization of nerve cells, inhibition of nerve firing, and presynaptic inhibition of transmitter release. Morphine acts at k receptors in lamina I and II of the substantia gelatinosa of the spinal cord, and decreases the release of substance P, which modulates pain perception in the spinal cord. Morphine also appears to inhibit the release of many excitatory transmitters from nerve terminals carrying nociceptive (painful) stimuli. 

Postsynaptically norepinephrine may interact with a- or 3-receptors, which couple with an adenylate (or guanylate) cyclase to initiate postsynaptic events (16,17). Presynaptic a- and 3-receptors have also been implicated in the modulation of transmitter release. While an adenylate cyclase has been associated with the presynaptic 3-receptor, the presynaptic a-receptor appears to be involved only with modulation of Ca++ fluxes (18,19). 

Figure 6-3. Lcx al integration of ANS control via modulation of transmitter release. In the example shown, release of norepinephrine from a sympathetic nerve ending is modulated by norepinephrine itself, acting on presynaptic autoreceptors, and by acetylcholine and angiotensin II. Many other modulators (see text) influence the release process.

Control of transmitter release is not limited to modulation by the transmitter itself. Nerve terminals also carry regulatory receptors that respond to many other substances. Such heteroreceptors may be activated by substances released from other nerve terminals that synapse with the nerve ending. For example, some vagal fibers in the myocardium synapse on sympathetic noradrenergic nerve terminals and inhibit norepinephrine release. Alternatively, the ligands for these receptors may diffuse to the receptors from the blood or from nearby tissues. Some of the transmitters and receptors identified to date are listed in Table 6-4. Presynaptic regulation by a variety of endogenous chemicals probably occurs in all nerve fibers. 

K+ channels are responsible for setting the resting membrane potential and for the repolarizing phase of action potentials. In addition, K+ channels mediate afterhyperpolarizations to terminate periods of high neuronal activity and to modulate firing rates. When located in presynaptic nerve terminals, these actions of K+ channels will contribute to the regulation of transmitter release. In fact, most types of the huge superfamily of K+ channels, in particular delayed rectifier, fast transient, and Ca2+-sensitive K+ channels, have been found in a variety of nerve terminals and... 

Engelman HS, Anderson RL, Daniele C, MacDermott AB (2006) Presynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors modulate release of inhibitory amino acids in rat spinal cord dorsal horn. Neuroscience 139 539 Engelman HS, MacDermott AB (2004) Presynaptic ionotropic receptors and control of transmitter release. Nat Rev Neurosci 5 135 45... 

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