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Presynaptic receptors play an important role - typically inhibitory--in modulating the strength of synaptic transmission in the brain. Recent studies now reveal that neurotransmitters can enhance synaptic strength by activating ligand-gated ion channels in presynaptic nerve endings.
Presynaptic receptors have recently been identified on nerves supplying vascular smooth muscle. Renin is stored in juxtaglomerular cells in the wall of the afferent glomerular arteriole and the JG cell is probably derived from vascular smooth muscle. Nervous stimuli exert an important influence on release of renin, but the nature of the receptors involved is not agreed. We propose that there are presynaptic receptors associated with the JG apparatus as with vascular muscle and that a mechanism of this sort gives a better account of data on renin release.
The release of noradrenaline from nerve terminals is modulated by a variety of presynaptic receptors. These receptors belong to one of the following three receptor superfamilies: transmitter-gated ion channels, G protein-coupled receptors (GPCR), and membrane receptors with intracellular enzymatic activities. For representatives of each of these three superfamilies, receptor activation has been reported to cause either an enhancement or a reduction of noradrenaline release. As these receptor classes display greatly diverging structures and functions, a multitude of different molecular mechanisms are involved in the regulation of noradrenaline release via presynaptic receptors. This review gives a short overview of the presynaptic receptors on noradrenergic nerve terminals and summarizes the events involved in vesicle exocytosis in order to finally delineate the most important signaling cascades that mediate the modulation via presynaptic receptors. In addition, the interactions between the various presynaptic receptors are described and the underlying molecular mechanisms are elucidated. Together, these presynaptic signaling mechanisms form a sophisticated network that precisely adapts the amount of noradrenaline being released to a given situation.
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Experiments on two different inhibitory presynaptic receptor systems are presented. 1. Superfused and electrically stimulated brain slices are a widely used experimental model to study the release of noradrenaline and its modulation by inhibitory alpha-2 adrenoceptors. By using a minisuperfusion chamber we succeeded in studying the simplest case of autoinhibition, i.e. the release of transmitter induced by a single pulse and two consecutive pulses, respectively. When electrical stimulation is performed using a single pulse, no autoinhibition is possible, whereas following stimulation with two pulses the transmitter released by the first pulse will inhibit the effect of the second pulse. By systemically varying the time interval between the two pulses the minimal time requirement for development of autoinhibition was determined to be 100 ms. Short pulse trains of high frequency such as 4 pulses within 30 ms circumvent autoinhibition and cause inhibition-free release by each applied pulse. The release of transmitter evoked in this way is not only free from autoinhibition but, in addition, easily measurable, which makes this method of stimulation very suitable for analyses at presynaptic receptors. By using this approach it became possible, for the first time, to determine dissociation constants of antagonists and agonists at the central presynaptic alpha-2 adrenoceptor without the distortion introduced by autoinhibition occurring during release. 2. There is a substantial body of evidence for a role of medullary serotonergic nerve cells in the regulation of blood pressure and heart rate. It is hypothesized that the serotonergic neurons project to the thoracic spinal cord exerting a tonic excitatory influence on presynaptic sympathetic neurons of the intermediolateral cell column. Experiments were performed in pentobarbital anaesthetized rats to reduce this excitatory tone by activating inhibitory autoreceptors which are located on the perikarya and dendrites on the serotonergic cells and which have been shown to belong to the 5-HT1A subtype. Local stereotactic injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) caused a decrease in mean arterial blood pressure (MAP) and heart rate (HR). The effects were blocked by pretreatment of the animals with the 5-HT1A antagonist spiroxatrine. Moreover, neurochemical lesioning of serotonergic neurons by intracisternal injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) abolished the effects of 8-OH-DPAT. Bilateral intraspinal injection of 5,7-DHT, which interrupts the medullo-spinal serotonergic pathway, markedly attenuated the effects of local intramedullary injection of 8-OH-DPAT.(ABSTRACT TRUNCATED AT 400 WORDS)
A review of the role of presynaptic receptors in the modulation of neurotransmitter release indicates two types of presynaptic receptors. By means of presynaptic inhibitory autoreceptors a neurotransmitter can regulate its own release. In addition, presynaptic receptors are acted upon by other endogenous compounds, either transmitters released from adjacent nerve terminals, blood-borne compounds or locally-formed substances, involved in trans-synaptic feed-back. Both types of presynaptic receptors may be involved in the physiological control of transmitter release and are the target of drug action, either as agonists or as antagonists.
This study investigated the identity of presynaptic receptors involved in dopaminergic modulation of purinergic transmission in peripheral tissues including isolated rat vas deferens and urinary bladder. Isometric muscle twitches were established in the two tissues by low frequency electric field-stimulation (0.05 Hz, 1-ms duration, and supramaximal voltage). Exposure to prazosin, 50 nmol l-1 (vas deferens), or atropine, 3 micromol l-1 (urinary bladder), had no effect on the developed twitches. In contrast, desensitisation of P2X-purinoceptors by alpha,beta-methylene ATP (alpha,beta-mATP, 30 micromol l-1) abolished the twitches in both tissues, confirming their purinergic origin. Dopamine (1.8x10(-7) to 4.2x10(-5) mol l-1) reduced the twitch response in a concentration-related manner. Yohimbine (alpha2-adrenoceptor antagonist, 0.3 micromol l-1) significantly (P<0.05) attenuated the inhibitory effects of dopamine and caused an upward shift in the concentration-response curves in the vas deferens and the urinary bladder. On the other hand, a blockade of DA2-dopaminoceptors by domperidone (1 micromol l-1) produced significant (P<0.05) reductions in dopamine responses only in rat vas deferens, with no effect in the urinary bladder. These data suggest that dopamine exerts inhibitory influences on purinergically-mediated muscle twitches in rat vas deferens and urinary bladder. More importantly, the nature of presynaptic receptors (alpha2-adrenergic and/or DA2-dopaminergic) involved in mediating dopamine effects is dependent on the tissue under investigation.
The possibility of interaction between neurotransmitter uptake mechanisms and presynaptic receptors regulating transmitter release was investigated using rat brain synaptosomes in superfusion. Various conditions were considered including: absence of substrate for the uptake with uptake potentially operative; absence of substrate and presence of uptake inhibitors; and uptake activated by added substrate, with or without uptake inhibitors. The release of [3H]-5-hydroxytryptamine ([3H]-5-HT) evoked by 15 mM KCl from cerebral cortex synaptosomes was inhibited by lysergic acid diethylamide. The 5-HT uptake inhibitors citalopram and chlorimipramine did not affect the inhibitory action of lysergic acid diethylamide. Clonidine decreased both the K+-evoked release of [3H]norepinephrine and that of [3H]-5-HT in cortical synaptosomes through the activation of presynaptic alpha-2 adrenoceptors. In superfusion conditions, the action of clonidine on [3H]norepinephrine release was not antagonized by the norepinephrine uptake inhibitors desipramine or cocaine; similarly, the inhibition of [3H]-5-HT release was unaffected when 5-HT uptake was blocked. The K+-evoked release of [3H]dopamine from striatal nerve terminals was potentiated by acetylcholine (ACh) through the activation of muscarinic presynaptic receptors. The action of ACh was not modified by the presence of nomifensine, a dopamine uptake inhibitor. Finally, in superfused cortical synaptosomes, the block of the high-affinity uptake of choline by hemicholinium-3 had no effect on the muscarinic autoreceptor-mediated inhibition of [3H]ACh release by ACh. Altogether the present results do not support the previously proposed idea that in nerve terminals a functional coupling may exist between uptake mechanisms and presynaptic receptors.
The ontogeny of dopamine (DA) presynaptic receptor regulation was examined neuropharmacologically in 7-, 14-, 21-, 28- and 35-day-old and adult rats. In striatum, gamma-butyrolactone (GBL) significantly increased DA levels as early as 7 days postnatally; apomorphine attenuated this increase beginning at 14 days postnatally. However, in olfactory tubercles, no increase in DA was observed after GBL until 21 days postnatally, and not until 35 days postnatally was apomorphine consistently able to attenuate this increase. Thus, DA presynaptic receptors in mesolimbic regions may mature several weeks later than in striatum.
The modulation of evoked transmitter release by presynaptic receptors was studied at an identified cholinergic synapse in the buccal ganglion of Aplysia. Two auto-receptors affecting acetylcholine release in opposite ways were identified. Additionally acetylcholine (ACh) release was found to be facilitated by the peptide FLRFamide and inhibited by histamine. Ca2+ channels appeared as the final effectors controlled by these non-cholinergic presynaptic receptors whereas the activation of cholinergic presynaptic receptors did not affect the Ca2+ influx. The intracellular pathway activated by FLRFamide receptors was investigated in detail. The facilitation of transmitter release induced by this peptide was prevented by bath application of H-7, a protein kinase C inhibitor. Moreover, a diacylglycerol analog mimicked the action of FLRFamide. These results suggest that activation of protein kinase C leading to the phosphorylation of Ca2+ channels could be the mechanism through which presynaptic FLRFamide receptors increase evoked quantal release of acetylcholine at this synapse.
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Recent evidence suggests that the functions of presynaptic metabotropic glutamate receptors (mGluRs) are tightly regulated by protein kinases. We previously reported that cAMP-dependent protein kinase (PKA) directly phosphorylates mGluR2 at a single serine residue (Ser843) on the C-terminal tail region of the receptor, and that phosphorylation of this site inhibits coupling of mGluR2 to GTP-binding proteins. This may be the mechanism by which the adenylyl cyclase activator forskolin inhibits presynaptic mGluR2 function at the medial perforant path-dentate gyrus synapse. We now report that PKA also directly phosphorylates several group III mGluRs (mGluR4a, mGluR7a, and mGluR8a), as well as mGluR3 at single conserved serine residues on their C-terminal tails. Furthermore, activation of PKA by forskolin inhibits group III mGluR-mediated responses at glutamatergic synapses in the hippocampus. Interestingly, beta-adrenergic receptor activation was found to mimic the inhibitory effect of forskolin on both group II and III mGluRs. These data suggest that a common PKA-dependent mechanism may be involved in regulating the function of multiple presynaptic group II and group III mGluRs. Such regulation is not limited to the pharmacological activation of adenylyl cyclase but can also be elicited by the stimulation of endogenous G(s)-coupled receptors, such as beta-adrenergic receptors.
Activation of different types of G-protein-linked and ionotropic presynaptic receptors has been shown to regulate neurotransmitter release throughout the central and peripheral nervous systems. In the case of G-protein-linked receptors, three major mechanisms have been suggested: (a) inhibition of Ca channels in the nerve terminal; (b) the activation of presynaptic K channels, resulting in a reduction in the effectiveness of the action potential; and (c) direct modulation of one or more components of the neurotransmitter vesicle release apparatus. In the case of ionotropic presynaptic receptors, inhibition of release may be achieved through depolarization of the terminal and inactivation of Na and Ca channels. Activation of presynaptic ionotropic receptors that are appreciably Ca permeable can also enhance the release of transmitters as a result of their ability to raise [Ca]i in the terminal directly. Many transmitters employ several of these mechanisms, thus allowing considerable flexibility in the presynaptic regulation of transmitter release.
Nondepolarizing muscle relaxants (MRs) diminish the indirectly evoked single twitch due to their binding to the postsynaptic receptors. Additionally, the MRs produce progressive diminution of successive twitches upon repetitive stimulation (fade). Our study addresses the generation of fade as observed under clinical situation. The study was conducted in two phases. In the clinical part, we have evaluated the time course of twitch depression and fade following the administration of several doses of three MRs (rocuronium, pancuronium, and cisatracurium). In the second part, we have modified our model of neuromuscular transmission to simulate the time course of twitch depression and fade. The MR was assumed to bind to a single site on the presynaptic receptor to produce fade. The rates of interaction with the presynaptic receptors were characterized in terms of the arbitrarily assigned equilibrium dissociation constant and the half-life for dissociation of the presynaptic complex. A method was developed to relate the release of acetylcholine to the occupancy of the presynaptic receptors. The strength of the first and the fourth twitch was calculated from the peak concentration of the activated postsynaptic receptors, i.e., of those receptors with both sites occupied by acetylcholine. Our results indicate that, while the affinity of the MR for the presynaptic receptor plays little role in the time course of fade, the rate of dissociation of the complex between the presynaptic receptors and the muscle relaxant may be critical in determining the time course of fade. Tentative estimates of this parameter are offered.
The quantitative analysis of receptor-mediated effects is based on experimental concentration-response curves in which an independent variable, the concentration of a receptor ligand, is linked with a dependent variable, the biological response. The steps that intervene between the ligand-receptor interaction and the subsequent biologic effect, i.e. modulation of transmitter release in our examples, are largely unknown. Nevertheless, the shape of a concentration-response curve may give some insights into the nature of the relation between receptor occupancy and ensuing response. The shape of the concentration-response curve can be evaluated by nonlinear regression analysis of the data points of the independent and dependent variable. If possible, the model applied should be mechanistically derived from a physical or chemical law, underlying the biological condition. For instance, the inherence of the Law of Mass Action allows to call the model mechanistic. The presence of spare receptors for an agonist must induce an alteration of the shape of the concentration-response curve as compared to a symmetric bimolecular concentration-binding curve. Evaluation methods which neglect the alteration of the geometrical form of concentration-response curves due to non-proportionality between receptor occupation and relative response do not seem appropriate to quantify spare receptors. The "general response function" may allow a mechanistic interpretation of the occupancy-response relationship. This function estimates roughly the number of "non-spare" receptors and of spare receptors on a functional unit that contribute to the response.
The release of transmitters at sympathoeffector junctions is not constant, but subject to modulation by a plethora of different mechanisms. In this respect, presynaptic receptors located on the sympathetic axon terminals are of utmost importance, because they are activated by exogenous agonists and by endogenous neurotransmitters. In the latter case, the transmitters that activate the presynaptic receptors of a nerve terminal may be released either from the very same nerve ending or from a different axon terminal, and the receptors involved are auto- and heteroreceptors, respectively. In terms of their structural and functional features, receptors of sympathetic axon terminals can be categorized as either ionotropic (transmitter-gated ion channels) or metabotropic (most commonly G protein-coupled) receptors. This review summarizes results on more than 30 different metabotropic and four different ionotropic receptors that have been found to control the amount of transmitter being released from sympathetic neurons. Each of these receptors may not only stimulate, facilitate, and reduce sympathetic transmitter release, respectively, but also interact with the functions of other receptors present on the same axonal varicosity. This provides a multitude of mechanisms that regulate the amount of sympathetic transmitter output. Accordingly, a sophisticated cross-talk within and between extra- and intracellular signals is integrated at axon terminals to adapt the strength of sympathoeffector transmission to a given situation. This will not only determine the function of the sympathetic nervous system in health and disease, but also therapeutic and untoward effects of drugs that bind to the presynaptic receptors in sympathetically innervated tissues.
The present study assessed the functional integrity of the serotonin (5-HT) presynaptic receptor in the spinal cord of aged (18-20 months) rats. Previous research determined that exogenous 5-HT and 5-HT1B agonists, in adult (3 months) rats, activated the 5-HT presynaptic receptor resulting in a dose-dependent decrease in 3H-5-HT release from spinal cord slices. Contrastively, exogenous 5-HT and the selective 5-HT1B agonist 1-(m-chlorophenyl) piperazine HCl (mCPP) produced a dose-dependent increase in depolarization-evoked 3H-5-HT release from spinal cord of aged rats. The selective 5-HT1A agonist 8-hydroxy-2(di-n-propylamino) tetralin (8-OHDPAT) increased 3H-5-HT release from aged rat spinal cord slices similar to results previously obtained from adult rat spinal cord slices. The inability of 5-HT and mCPP to inhibit 3H-5-HT release from spinal cord of aged rats indicates a functional change in the 5-HT presynaptic receptor in these animals. Possible mechanisms mediating this functional change are discussed.