Heteroreceptors function

Fig. 3 Autoreceptor versus heteroreceptor functions of a2-adrenoceptor subtypes, (a and b) Inhibition of electrically evoked [3H]-adrenaline release by the 012-agonist, medetomidine, from mouse brain cortex (a) or heart atria (b). In wild-type tissue specimens, medetomidine inhibited transmitter release by >90%. In tissues from a2AC-deficient mice, the agonist effect was absent (a, cortex) or significantly reduced (b, atria). Reproduced with permission from Trendelenburg et al. 2003b. (c) Overview of auto- and heteroreceptor functions of a2-adrenoceptor subtypes. For references, see text.

Studies have now started to clarify the role of histamine Hi and H2 receptors in the cardiovascular manifestations of anaphylaxis. However, histamine can activate H3 and H4 receptors [56, 57]. Levi and coworkers [58-60] identified H3 receptors as inhibitory heteroreceptors in cardiac adrenergic nerve endings. This suggests a mechanism by which endogenous histamine can activate norepinephrine release in normal and ischemic conditions [61,62]. The functional identification ofH3 receptors in the human heart [59] means that these receptors might be directly and/or indirectly involved in the cardiovascular manifestations of anaphylactic reactions. 

Histaminergic neurons can regulate and be regulated by other neurotransmitter systems. A number of other transmitter systems can interact with histaminergic neurons (Table 14-1). As mentioned, the H3 receptor is thought to function as an inhibitory heteroreceptor. Thus, activation of brain H3 receptors decreases the release of acetylcholine, dopamine, norepinephrine, serotonin and certain peptides. However, histamine may also increase the activity of some of these systems through H, and/or H2 receptors. Activation of NMDA, p opioid, dopamine D2 and some serotonin receptors can increase the release of neuronal histamine, whereas other transmitter receptors seem to decrease release. Different patterns of interactions may also be found in discrete brain regions. 

Dopamine acts on G-protein-coupled receptors belonging to the D1 -family of receptors (so-called D1-like receptors , or DlLRs, comprised of Dl- and D5-receptors), and the D2-family of receptors ( D2-like receptors , or D2LRs comprised of D2-, D3- and D4-receptors). Dl LRs stimulate adenylate cyclase activity and, possibly, also phosphoinosit-ide hydrolysis, while D2LRs reduce adenylate cyclase activity. In the striatum, DlLRs are predominately associated with medium spiny neurons of the direct pathway, while D2LRs have been found as autoreceptors on dopaminergic terminals, as heteroreceptors on cholinergic interneurons, and on indirect pathway neurons. In the SNr, DlLRs are located on terminals of the direct pathway projection, while D2LRs appear to function as autoreceptors. 

FIGURE 5—44. This figure shows how norepinephrine can function as a brake for serotonin release. When norepinephrine is released from nearby noradrenergic neurons, it can diffuse to alpha 2 receptors, not only to those on noradrenergic neurons but as shown here, also to these same receptors on serotonin neurons. Like its actions on noradrenergic neurons, norepinephrine occupancy of alpha 2 receptors on serotonin neurons will turn off serotonin release. Thus, serotonin release can be inhibited not only by serotonin but, as shown here, also by norepinephrine. Alpha 2 receptors on a norepinephrine neuron are called autoreceptors, but alpha 2 receptors on serotonin neurons are called heteroreceptors. 

Abstract Presynaptic receptors for dopamine, histamine and serotonin that are located on dopaminergic, histaminergic and sertonergic axon terminals, respectively, function as autoreceptors. Presynaptic receptors also occur as heteroreceptors on other axon terminals. Auto- and heteroreceptors mainly affect Ca2+-dependent exocytosis from the receptor-bearing nerve ending. Some additionally subserve other presynaptic functions. 

Blockade of histamine autoreceptors increases histamine synthesis and release and may support higher CNS functions such as arousal, cognition and learning. Peripheral histamine heteroreceptors on C liber and on postganglionic sympathetic fiber terminals diminish neuropeptide and noradrenaline release, respectively. Both inhibititory effects are beneficial in myocardial ischemia. The inhibition of neuropeptide release also explains the antimigraine effects of some agonists of presynaptic histamine receptors. 

Our knowledge of presynaptic dopamine and serotonin receptors dates back to the 1970s (Famebo and Hamberger 1971). Presynaptic histamine receptors were discovered in 1983 (Arrang et al. 1983). Presynaptic dopamine receptors occur as autoreceptors, i.e., on dopaminergic axon terminals, and as heteroreceptors on nondopaminergic axon terminals. By analogy the same holds true for presynaptic histamine and serotonin receptors. The early days of the dopamine autoreceptors were stormy, but the controversies were finally solved (see Starke et al. 1989). The main function that presynaptic receptors affect is transmitter release, which in this article means Ca2+-dependent exocytosis. However, some receptors discussed in... 

Gothert M, Garbarg M, Hey JA, Schlicker E, Schwartz JC, Levi R (1995) New aspects of the role of histamine in cardiovascular function identification, characterization, and potential pathophysiological importance of H3 receptors. Can J Physiol Pharmacol 73 558-64 Gothert M, Fink K, Frolich D, Likungu J, Molderings G, Schlicker E, Zentner J (1996) Presynaptic 5-HT auto- and heteroreceptors in the human central and peripheral nervous system. Behav Brain Res 73 89-92... 

The review by Cartmell and Schoepp (2000) covered almost exhaustively the field of mGluRs that are localized on nonglutamatergic terminals and regulate as presynap-tic heteroreceptors the release of various transmitters this section of my chapter will therefore be essentially restricted to recent aspects of the functional pharmacology of presynaptic metabotropic glutamate heteroreceptors. 

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). 

When a stimulus depolarises the transmembrane potential in a spiking axon above the threshold level, an all-or-none action potential in a spiking axon is activated. The action potential propagates unattenuated to the nerve terminal where ion fluxes activate a mobilisation process leading to transmitter secretion.3 The neurotransmitter binds reversibly to receptor proteins embedded in the membrane of a neuron, which triggers a certain effect. There are two types of receptors known, presynaptic receptors or autoreceptors which are present on the neurotransmitter releasing neurons , and postsynaptic or heteroreceptors, which are present on the neurotransmitter receiving neuron . The former are supposed to perform a feed-back function, and slow down the release of neurotransmitter from these neurons when they are stimulated.4... 

Receptors on soma, dendrites, and axons of neurons respond to neurotransmitters or modulators released from the same neuron or from adjacent neurons or cells. Soma-dendritic receptors are located on or near the cell body and dendrites when activated, they primarily modify functions of the soma-dendritic region such as protein synthesis and generation of action potentials. Presy-naptic receptors are located on axon terminals or varicosities when activated, they modify functions such as synthesis and release of transmitters. Two main classes c presynaptic receptors have been identified on most neurons, including sympathetic and parasympathetic terminals. Heteroreceptors are presynaptic receptors that respond to neurotransmitters, neuromodulators, or neurohormones released from adjacent neurons or cells. For example, NE can influence the release of ACh from parasympathetic neurons by acting on and receptors, whereas ACh can... 

Heteroreceptors (HRs), like autoreceptors, can either suppress (inhibitory autoreceptors such as the tt2-adrenergic) or enhance the release of neurotransmitters. They are termed heteroreceptors since they are activated by neurotransmitters (e.g. norepinephrine) different from those produced by the nerve on which they are located (e.g. serotonergic). There might be numerous different heteroreceptors that bind various neurotransmitters on a single nerve. Table 1.2 summarizes some of the main modulating mechanisms relevant to intact functioning of the presynaptic nerve. Psychotropic medications can either enhance or suppress many of the major processes or modulatory events listed in this chapter. - ... 

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