Vol. 52, Issue 1, 63-90, March 2000

Role of High-Affinity Receptors and Membrane Transporters in Nonsynaptic Communication and Drug Action in the Central Nervous System

E. Sylvester Vizi

Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary

I. Introduction
II. Modulation of Neurochemical Transmission: Role of Receptors and Plasma Membrane Transporters
    A. Presynaptic Receptor-Mediated Modulation of Transmitter Release
        1. Heteroreceptor-Mediated Control of Transmitter Release.
        2. Autoreceptor-Mediated Control of Transmitter Release.
        3. Presynaptic Ionotropic Receptors.
        4. Presynaptic Metabotropic Receptors.
        B. Plasma Membrane Transporters.
        1. Characteristics of Transporters.
        2. Substrate Selectivity.
III. Nonsynaptic Varicosities
IV. Extracellular Space as a Communication Channel of Nonsynaptic Interaction
V. Nonsynaptically Expressed Receptors and Membrane Transporters of High Affinity as Therapeutic Targets
    A. Nonsynaptic Receptors
    B. Nonsynaptic Transporters
    C. Nonsynaptic Interaction between Neurons without Receptors
VI. Clinical Implications
VII. Summary
Acknowledgments
References

Neurochemical and morphological evidence has shown that some neurotransmitters or substances may be released from both synaptic and nonsynaptic sites for diffusion to target cells more distant than those observed in regular synaptic transmission. There are functional interactions between neurons without synaptic contacts, and matches between release sites and localization of receptors sensitive to the chemical signal are exceptions rather than the rule in the central nervous system. This also indicates that besides cabled information signaling (through synapses), there is a "wireless" nonsynaptic interaction between axon terminals. This would be a form of communication transitional between discrete classical neurotransmission (in Sherrington's synapse) and the relatively nonspecific neuroendocrine secretion. Recent findings indicate that in addition to monoamines (norepinephrine, dopamine, serotonin), other transmitters, such as acetylcholine and nitric oxide (NO), may also be involved in these nonsynaptic interactions. It has been shown that NO, an ideal mediator of nonsynaptic communication, can influence the function of uptake carrier systems, which may be an important factor in the regulation of extracellular concentration of different transmitters. This review will focus on the role of nonsynaptic receptors and transporters in presynaptic modulation of chemical transmission in the central nervous system. The nonsynaptic interaction between neurons mediated via receptors and transports of high affinity not localized in synapses has the potential to be an important contributor to the properties and function of neuronal networks. In addition, it will be suggested for the first time that the receptors and transporters expressed nonsynaptically and being of high affinity are the target of drugs taken by the patient.