Vol. 54, Issue 1, 43-100, March 2002

Fine Tuning of Sympathetic Transmitter Release via Ionotropic and Metabotropic Presynaptic Receptors

Stefan Boehm and Helmut Kubista

Institute of Pharmacology, University of Vienna, Vienna, Austria

I. Introduction
II. Anatomical and Functional Organization of the Sympathetic Nervous System
III. Methodological Considerations
IV. Ionotropic Receptors
    A. Ionotropic Autoreceptors
        1. P2X Nucleotide Receptors.
    B. Ionotropic Heteroreceptors
        1. Nicotinic Acetylcholine Receptors.
        2. -Aminobutyric Acid_A Receptors.
        3. Glycine Receptors.
        4. Serotonin 5-Hydroxytryptamine₃ Receptors.
V. Metabotropic Receptors
    A. Metabotropic Autoreceptors
        1. ₂-Adrenoceptors.
        2. P2Y Nucleotide Receptors.
        3. Neuropeptide Y Y2 Receptors.
    B. Metabotropic Heteroreceptors
        1. ₂-Adrenoceptors.
        2. Muscarinic Acetylcholine Receptors.
        3. Adenosine A₁ and A₂ Receptors.
        4. Angiotensin II AT₁ Receptors.
        5. Bradykinin B₂ Receptors.
        6. Cannabinoid CB₁ Receptors.
        7. Dopamine Receptors.
        8. Endothelin Receptors.
        9. -Aminobutyric Acid_B Receptors.
        10. Histamine H₃ Receptors.
        11. Imidazoline Receptors.
        12. Natriuretic Peptide Receptors.
        13. Opioid -, -, and µ-Receptors.
        14. Prostanoid Receptors.
        15. Serotonin 5-Hydroxytryptamine₁ Receptors.
        16. Somatostatin Receptors.
        17. Receptors for Vasoactive Intestinal Peptide and Pituitary Adenylyl Cyclase-Activating Peptides.
        18. Additional Receptors.
VI. Basic Mechanisms of Vesicular Sympathetic Transmitter Release
    A. Ionotropic Mechanisms
    B. Metabotropic Mechanisms
VII. Signaling Mechanisms of Presynaptic Ionotropic Receptors
    A. Signaling Mechanisms of Ligand-Gated Anion Channels
    B. Signaling Mechanisms of Ligand-Gated Cation Channels
VIII. Signaling Mechanisms of Presynaptic Metabotropic Receptors
    A. Signaling Mechanisms of Facilitatory Metabotropic Receptors
    B. Signaling Mechanisms of Inhibitory Metabotropic Receptors
IX. Interactions between Presynaptic Receptors
    A. Examples of Interaction
    B. Mechanisms of Interaction
X. Conclusion: Signal Integration in the Sympathetic Varicosity
Acknowledgments
References

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.