Frank A Redegeld Department of Pharmacology and Pathophysiology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

Henk Van Loveren, Laboratory of Pathology and Immunobiology, National Institute of Public Health and the Environment, Bilthoven, The Netherlands

In addition to its role in neurological processes, the biogenic amine 5-hydroxytryptamine (5-HT) or serotonin (Figure 1) can be active as a vasoactive amine causing vascular permeability, smooth muscle contraction, and also playing an important role in the regulation of immunological responses. The following entry will summarize the most relevant information on storage and release of this catecholamine


Figure 1 Structure of 5-hydroxytryptamine (serotonin).

by cells that belong to the immune system, or are associated with that system, and on the activity of serotonin in the context of the immune system.

Serotonin is released by rodent but not human mast cells, and also by basophils, platelets, and certain T cell populations with serotonin-positive granules. Upon activation, mast cells release a variety of mediators, including serotonin. Release occurs by a noncytolytic process that under most circumstances can be described as granule exocytosis. A large series of agents (secretagogues) are able to induce this release. The most well-studied example of mast cell release is induced by protein allergens in immunoglobulin E (IgE)-sensitized mast cells participating in hypersensitivity reactions of the immediate, or anaphylactic type. Upon atopic sensitization, allergens induce specific antibodies of the IgE class (so-called anaphylactic, or reaginic, or cytotropic IgE antibodies). Mast cells possess surface membrane receptors that specifically bind the Fc part of the IgE antibody with high affinity. Bridging of these Fc receptors by cross-linking of the bound IgE by the bi- or multivalent allergen, or anti-IgE, or otherwise, results in a transmembrane signal that causes activation of membrane-associated enzymes, leading ultimately to degranulation and release of mediators, among which is serotonin.

Apart from the classical IgE-mediated release of mast cell products, activation and mediator release can be initiated by a number of other potent secreta-gogues. Among those are products generated during inflammatory reactions such as the anaphylatoxins C3a and C5a which are produced during complement activation, and leukocyte-derived factors, i.e. products released from neutrophils, eosinophils, macrophages and lymphocytes, some of which arc IgE-binding factors. Complement receptors have been demonstrated on mast cells. Other, non-immunological, secretagogues include several neuropeptides such as substance P, somatostatin, neurotensin and nerve growth factor, which is interesting in view of the fact that there is a close anatomical relationship between mast cells and nerve fibers. Further stimuli are opioids, smooth muscle relaxants and other drugs, highly charged basic polypeptides, the calcium ionophore A23187, compound 48/80, dextran and enzymes like chymotrypsin and phos-pholipase. Also physical factors like ultrasound, heat, cold, pressure and physiological conditions such as hypoxia, osmotic alterations and stress are considered stimuli for mast cell activation.

The ultrastructure of anaphylactic degranulation of mast cells in various species has been described in derail both in vivo and in vitro. Briefly, degranulation proceeds by swelling of the granules, converting the electron-dense granule contents into a more particulate appearance, and fusion of perigran-ular membranes with each other and with the plasma membrane. Thus, extensive channels, labyrinths or vacuoles opening to the exterior are formed, from which the granular contents are extruded into the environment. Degranulation requires calcium uptake and consumption of metabolic energy, i.e. it is a non-cytolytic process. After degranulation, mast cells still possess a full complement of cytoplasmic organelles, recover and regranulate.

In basophils and also in mast cells, a process of exocytosis that differs from the process described above has been described called 'piecemeal' degranu lation. Here, partial release of granular contents occurs by a vesicular transport mechanism involving budding of loaded vesicles from the granule membrane, transit through the cytoplasm, and fusion of these transport vesicles with the plasma membrane. This mechanism is thought to cause mild or gradual and time-spaced degranulation from basophils and differential release of serotonin from mast cells in mice. Differential release of serotonin can occur if mast cells are pretreated with certain drugs (such as the tricyclic antidepressant amitriptyline) and may occur in vivo in delayed-type hypersensitivity (DTH) responses.

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