Modulation of classical neurotransmitter systems by σ receptors

Document Type

Journal Article

Publication Date

1-1-2007

Journal

Sigma Receptors: Chemistry, Cell Biology and Clinical Implications

DOI

10.1007/978-0-387-36514-5_10

Abstract

© 2007 Springer Science-KBusiness Media, LLC. All rights reserved. Althougii actions of σ receptors on several physiological processes (Chapters 11-18) have been described, very little is known about a receptormediated neurotransmission. This is largely due to the lack of unequivocal identification of an endogenous ligand. Recent evidence has implicated neurosteroids as potential endogenous transmitters at σ receptors (reviewed in Chapter 1). Despite these recent provocative data, more information is available regarding the modulation of other, classical neurotransmitter systems via activation of σ receptors by prototypical and novel a receptor ligands. Even when ligands that have been well characterized in radioligand binding assays are used, there is not complete agreement on which drugs act as agonists, and which as antagonists, σ receptors are unlikely to be "classical" transmitter receptors. The data reported in the ion channel studies of Jackson and colleagues (1-3) as well as those from the ankyrin/IP3 receptor dynamics studies of Su and colleagues (4,5) clearly demonstrate that protein-protein interactions are important in a receptor signaling, and at least some a receptor-mediated processes probably rely on the a receptor associating with one or more additional proteins to cause a physiological effect. Such interactions might or might not follow the agonist/antagonist relationships that are the hallmark of traditional pharmacology. Another often debated aspect of CT receptor modulation of neurotransmitter function is that of G protein coupling. While the cloned Oi receptor protein is too small and does not have the appropriate site for coupling directly to a G protein, several reports of G protein- or pertussis toxin-sensitivity of a agonistmediated processes have been reported (6). However, most studies show no effect of guanyl nucleotides on the binding of haloperidol or (+)-pentazocine to σ receptors (7). Recent evidence associating a\ receptor activation with phospholipase C (PLC)/protein kinase C (PKC) pathways may partially explain these findings, as some G proteins involved in PLC function are pertussis toxin sensitive (8). Even though there is not complete agreement in various studies about identification of a agonists versus antagonists, the evidence shows that some drugs that bind to σ receptors antagonize the actions of others that also bind, so at some level, receptor-like properties exist. Discrepancies also likely arise from the probability that there are more a receptor subtypes than have been unequivocally identified, as well as from the possibility that a receptormediated signaling is complex and multiple pathways may be activated depending upon the neuron studied. Additionally, tonic actions of endogenous ligand probably influence the experimental results. In this chapter, modulation of several well-characterized transmitter systems via a receptor-mediated actions will be described, and where these processes have been linked to signaling pathways, those will be mentioned in an attempt to develop a unifying picture of possible a receptor function. We will concentrate on direct actions of a ligands on central systems. Much work has been done on central effects of peripherally administered CT ligands, and these studies are critically important in the development of therapeutic strategies that might utilize CT ligands in the future. However, since many steps are likely to exist between peripheral administration and central neuronal activity, primarily the direct effects on central nervous system neurons or cells in culture will be addressed here, except in cases in which peripheral and local central administration of the a drugs produced similar results. σ receptors are distributed throughout the central nervous system as well as in peripheral tissues. Bouchard and Quirion (9) studied autoradiographically the distribution of 0\ and CT2 receptors as labeled by [^H](+)-pentazocine, and [^H]di-o-tolylguanidine (DTG) in the presence of unlabeled (+)-pentazocine, respectively. They found enrichment of a\ binding in brainstem nuclei, especially the oculomotor, trigeminal and facial cranial nerve nuclei. The red nucleus and the substantia nigra were also highly labeled, as was the pyramidal layer of the hippocampus. 02 Sites were generally in lower density than ai, but several areas of brain, including substantia nigra pars reticulata, central gray, oculomotor nucleus, nucleus accumbens, cerebellum and motor cortex showed a relatively greater density of a2, as compared to a\, sites. These data vary somewhat from those of Leitner et al. (10) who, using homogenate binding, observed a ratio of greater than 1.0 for Oi to 0\ receptors in all brain areas examined. In their study, the highest densities of 0\ receptors were found in hindbrain and midbrain, while CT2 receptors were enriched in those areas in addition to cortex and cerebellum. Alonso et al. (11) used an antibody raised to amino acids 143-162 of the aj protein to label ai sites in rat brain. They detected high CT] binding in the granular layer of the olfactory bulb, several hypothalamic nuclei, the septum, the central gray, and motor nuclei of the hindbrain and the dorsal horn of the spinal cord. In general, expression of ai receptor mRNA coincided with distributions first described by quantitative autoradiography (12). Logically, one might examine regulation of transmitter systems in areas of high a receptor density, but several areas where a receptor-mediated effects have been described are not especially enriched in σ receptors, a reminder that a few receptors are capable of profound effects if the amplification system is robust. Subcellularly, σ receptors have been localized to plasma membrane, endoplasmic reticulum (ER), mitochondria and cytoplasm (11,13). Trafficiiing of σ receptors has been demonstrated in guinea pig hypoglossal neurons (14) and NG108 cells (15), and by extrapolation, is likely to occur in other neurons and cells as well. Trafficking allows for regulation of multiple cellular processes, and subsequently of neural systems at several levels. An issue in the a receptor field has been that while many studies demonstrate a profile of a variety of CT ligands with a rank order of potency identical or nearly identical to the binding affinity at σ receptors, supporting actions of these ligands via σ receptors, the potency of the compounds in physiological assays is orders of magnitude lower than that in binding assays. Ideally, one would be able to see effects of a ligands at concentrations that are commensurate with their affinities at o receptors in radioligand binding assays. Most a-active compounds bind with affinities in the nanomolar to low micromolar range, whereas in many reports on function, concentrations required to observe effect are in the micromolar to high micromolar range. Explanations offered for this phenomenon have included a compelling argument for pH and cell permeability (16), intermediate steps, and the disruption of accessory protein ensembles required for function by preparation of tissue for binding assays. Yet, correlation of potency with Ki in some assays is quite direct. For instance, in regulation of catecholamine release, IC50 values for regulation by σ receptors are virtually identical to Ki values in binding studies (6,17). This would imply that pH and its effects on protonation status are less in important in some physiological functions of σ receptors, and perhaps that those receptors mediating functions at concentrations similar to Kj values occur via σ receptors that are located on the plasma membrane. In contrast, those actions that require binding to an intracellular CT receptor, such as one on the ER, would require a non-protonated form of the ligand, which would be necessary for it to cross the cell membrane to gain access to intracellular receptors (e.g. 18). One way that CT ligands could exert their effects on classical neurotransmitter systems is via direct modification of ion channels (see Chapter 7). Since theoretically all neurons bear potassium and calcium channels, both of which are modified by application of a ligands, if a particular neuron also bears σ receptors, effects of a ligands could be quite profound, a Receptor activation has also been linked to intracellular calcium homeostasis, a critical regulator of cellular function (15,18). For example, we have demonstrated that (+)pentazocine and several neurosteroids enhance bradykinin-induced increases in intracellular calcium in SH-SY5Y cells, and these enhancements are blocked by haloperidol (82). Again, such effects could mediate a regulation of multiple neurotransmitter systems.

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