La plaqueta como marcador biológico periférico de la función serotoninérgica neuronal

• Autores: Maria del Carmen Lara Muñoz, Julia Moreno Moreno, Carlos A. Torner Aguilar, María Guadalupe Campos
• Localización: Salud mental, ISSN 0185-3325, Vol. 28, Nº. 3, 2005, págs. 79-87
• Idioma: español
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• Resumen
  • español

    De todos los neurotransmisores, la serotonina (5-hidroxi-triptamina; 5-HT) muy probablemente ha sido la más estudiada en la neuropsicofarmacología. El interes por este neurotransmisor se debe a la evidencia de la alteración de los sistemas serotoninérgicos en pacientes deprimidos, así como en varios trastornos de conducta, como la agresividad, la impulsividad y los intentos de suicidio.

    Las plaquetas se han propuesto como un marcador biológico periférico del funcionamiento de las neuronas serotoninérgicas centrales debido a las similitudes que comparten en los mecanismos de captura, almacenamiento y liberación de serotonina, y a que los receptores 5-HT2A estan presentes en las membranas de ambos tipos celulares. El sistema serotoninérgico de las plaquetas tiene cuatro componentes principales: 1. un mecanismo de captura, 2. organelos de almacenamiento intracelular, 3. receptores serotoninérgicos en la membrana plasmática, y 4. una enzima mitocondrial para su metabolismo (la monoaminooxidasa, MAO). Todos estos elementos tienen similitudes fisiológicas y fisiopatológicas con el sistema serotoninérgico neuronal.

    En el Sistema Nervioso Central (SNC), la 5-HT actúa de manera predominante como un neurotransmisor de tipo inhibitorio. El triptófano, precursor para su síntesis, es convertido por la triptófano hidroxilasa en 5-hidroxitriptófano (5-HTTP), el cual a su vez se transforma rápidamente en 5-HT por la acción de la L-ácido aromático descarboxilasa. Sin embargo, las plaquetas no poseen triptófano hidroxilasa, por lo cual no se sintetizan 5-HT y sólo pueden tener funciones de captura, almacenamiento y liberación de 5-HT.

    La liberación de serotonina por las neuronas cumple funciones de neurotransmisor, mientras que la serotonina plaquetaria es una reserva de lento recambio que puede ser liberada de las plaquetas por exocitosis, y participa en la activación de las plaquetas, lo que facilita su agregación en el proceso de coagulación.

    Para determinar la señal neurotransmisora en el SNC, la serotonina es capturada del espacio sináptico por un sistema proteico impulsado por un gradiente de protones que consume ATP. La 5-HT recapturada puede seguir dos rutas: ser degradada por la MAO a ácido 5-hidroxi-indolacético (5-HIAA) o puede ser introducida en las vesículas secretoras para ser nuevamente liberada al espacio sináptico.

    La captura de 5-HT por las plaquetas ocurre de dos maneras: por difusión pasiva y por un mecanismo activo. El mecanismo activo está mediado por una proteína similar al transportador de 5-HT neuronal, que requiere de energía y de la presencia de Na+ y Cl-. Este sistema plaqueteraio de captura tiene un grado de afinidad similar al del sistema neuronal. Hay evidencia experimental de que la proteína transportadora de serotonina del cerebro y las plaquetas, está codificada por el mismo gen, y el transportador plaquetario tiene además las mismas características funcionales y farmacológicas que el transportador neuronal.

    Receptores serotoninérgicos Los receptores 5-HT1A presinápticos son autoreceptores somatodendríticos. Ejercen un control inhibitorio de la liberación de serotonina y, por lo mismo, cuando disminuye su efecto por una regulación a la baja (down regulation) se produce un aumento de la liberación de serotonina. Los receptores 5-HT1 postsinápticos desempeñan un papel en la termorregulación corporal. Los autoreceptores 5-HT1D presinápticos actúan como reguladores de la liberación de 5-HT, bloquenado la liberación de 5-HT. Estos receptores no se encuentran en las plaquetas.

    Receptores postsinápticos 5-HT2 Tiene varios subtipos: 5-HT2 A, B y C; son glucoproteínas y han sido caracterizados por medio de la identificación del código genético del cADN de estos receptores. Cuando el receptor 5-HT2A postsináptico es ocupado por la serotonina, provoca la producción de segundos mensajeros, los que estimulan la síntesis de proteínas intracelulares denominadas factores de transcripción; éstas regulan a su vez ña expresión de varios genes neuronales. Aunque se ha propuesto que en las membranas plaquetarias los receptores 5-HT2A metabotrópicos, las alteraciones de densidad y afinidad, sus respuestas a segundos mensajeros, y su implicación en la neurotransmisión, no han podido explicarse bien mediante el modelo plaquetario.

    Los receptores 5-HT3 aon loa únicos receptores de monoaminas que funcionan como canales iónicos. Estos receptores se sitúan sobre terminaciones parasimpáticos en el tubo digestivo, y en el SNC se encuentran con gran densidad en el núcleo del has solitario y en el área postrema. Son responsables de varios efectos secundarios de los inhibidores selectivos de la recaptura de serotonina (ISRS) en el SNC, así como en el intestino y otras regiones donde se encuentran estos receptores. No se localizan en las plaquetas.

    Subpoblación 5-HT4-7 Se encuentran distribuidos por todo el cuerpo. Estimulan las secreciones del tubo digestivo y facilitan los reflejos peristálticos del mismo. No se ha explorado su participación en la neurotransmisión y su disfunción en trastornos depresivos.

    Estas características han llevado a proponer a las plaquetas como modelos parciales para el estudio de la serotonina neuronal. Como Alfred Pletscher expresó: ¿si bien lo incompleto del modelo exige cuidado en su aplicación, podría tener la ventaja de la simplicidad relativa¿.

  • English

    Among all neurotransmitters, serotonin or 5-hydroxi-triptamine (5-HT) is probably the most studied in neuropsychopharmacology. Interest in this neurotransmitter is due to cumulative evidences showing that neuronal serotonergic systems are altered in depressed patients, as well as in several behavior dysfunctions like aggressiveness, impulsiveness, and suicide attempts, among others. Also, specific agonists and antagonists have been synthesized, which has enabled the characterization of the serotonergic receptor subtypes. Furthermore, highly selective inhibitors ofserotonin uptake have been developed, and these are capable of working in the synaptic terminals, as well as in other cell systems, such as platelets. This has allowed for the understanding and characterization of the action mechanisms of diverse psychoactive drugs interacting with the serotonergic system.

    Platelets have been proposed as an outlying model resembling that of serotonergic neurons due to the similarities they present in the uptake, storage, and serotonin release mechanisms, as well as the presence in platelet membranes of serotonin 5-HT2A receptors. The platelets have a serotonergic system consisting of four main components: 1. an uptake mechanism, 2. intracellular storage organelles, 3. serotonergic receptors in the plasmatic membrane, and 4. a mitochondrial enzyme, the monoamine oxidase (MAO), which metabolizes serotonin. All these elements show physiologic similarities with the neuronal serotonergic system.

    Serotonergic similarities in neurons and platelets In the Central Nervous System (SNC) serotonin acts mainly as an inhibitory neurotransmitter. The precursor for its synthesis is the aminoacid tryptophan. This is taken from the blood to the cerebral interstice, where it is taken up by the nervous terminals and converted into 5-hidroxytryptophan (5-HTP) by the enzyme tryptophan hydroxilase. The conversion to 5-HTP is a key regulatory step in serotonin synthesis, and is converted quickly in 5-HT by the action of the aromatic L-acid descarboxilase. However, platelets do not synthesize 5-HT, since they do not possess tryptophan hydroxilase. Thus they only display uptake, storage, and serotonin release functions.

    Serotonin actions The neurotransmitter functions of neuronal serotonin, generally inhibitory, depend on the serotonergic receptor characteristics it interacts with. Its action mechanism can be mediated through second messengers (metabotrophic receptors) or through a direct action over ionic channels (ionotrophic receptors). In the platelets, serotonin is stored in a slow replacement depot, where it can be released from by exocythotic mechanisms. Serotonin participates in the platelet activation that allows for their aggregation to each other for blood clotting process.

    Serotonin uptake To stop the serotonin neurotransmitter function, neuronal serotonin is taken up from the synaptic cleft by transporter proteins. The serotonin neuronal uptake is impelled by a proton gradient that requires ATP. The 5-HT uptake can follow two paths: the 5-HT can be metabolized by the MAO into 5-hydroxy-indolacetic acid, or it can be reintroduced into release vesicles in order to be reutilized as a neurotransmitter.

    The serotonin uptake by platelets occurs either by passive diffusion or by active transport mechanisms. Under physiological conditions, the active uptake mechanism is the most effective. This uptake is mediated by proteins similar to the ones required for the neuronal serotonin uptake in the brain. It requires energy and the presence of Na+ and Cl-. The platelet uptake system has a relatively high affinity (Kd) for 5-HT, being similar in magnitude from platelets to neurons. The platelet storage of 5-HT is located mainly in the dense bodies and in the storage granules.

    Serotonin transporters in platelets and synaptic terminals The main form of ending a serotonergic transmission pulse is by taking up 5-HT molecules from the synaptic cleft directed to reduce the serotonin concentration, which then stops the serotonergic neurotransmission.

    The uptake process involves a molecular recognition of 5-HT by the transporter, its binding, and passing through the membrane to be released within the cellular. Serotonin molecules bound to its transporter protein cross through the membrane using Na+ as a driving force. The return ofthe transporter to its original position requires K+ as the driving force to step this protein toward its original position. When a selective serotonin reuptake inhibitor is administered, the 5-HT concentration increases in the synaptic cleft, which enhances serotonin neurotransmission. This increase induces a down regulation cascade of both: serotonin autoreceptors (presynaptic) and postsynaptic receptors, that may finally reestablish the resting state of the neuron.

    It has been confirmed that the protein for neuronal as well as platelet serotonin uptake transport are synthesized by the same gene. Experimental evidence has shown that the platelet transporter presents the same functional and pharmacological characteristics than the neuronal transporter.

    Serotonergicreceptors Seven types of pre and post synaptic serotonin receptors, which have also several subtypes, have been characterized.

    Pre and post synaptic 5-HT 1 receptors . The 5-HT1 receptors are involved in both pre and post synaptic serotonergic neurotransmission. The presynaptic 5-HT1A receptors are autoreceptors. Due to their localization in the cellular body and in the dendrites, they have been named somatodendritic autoreceptors, which control the serotonin release. The postsynaptic receptors may play a role in hypothalamic thermoregulation. The presynaptic 5-HT1D receptors are autoreceptors that perform a regulation by blocking the 5-HT release. These receptors are not synthesized in platelets.

    Postsynaptic 5-HT 2 receptors . The 5-HT2 receptor subtypes are 5-HT2A,BandC. When postsynaptic 5-HT2Areceptors are bound to serotonin, they drive the transduction of neuronal impulses through the production of second messengers within the postsynaptic neuron. These second messengers induce the synthesis of intracellular proteins denominated transcription factors, which may regulate the expression of several neuronal genes. Platelet 5-HT2A receptors correspond to the neuronal 5-HT2A metabothropic receptors and induce alterations in platelet density and affinity.

    5-HT 3 receptors . These receptors were originally described in the periphery, specifically as part of the enteric nervous system. In the CNS 5-HT3 receptors are densely present in the solitary tract nucleus and in the area postrema. These receptors are the onlymonoaminergic receptors consistingofionic channels operated by aminergic neurotransmitters. The stimulation of 5-HT3 receptors is responsible of several secondary effects of the selective inhibitors of serotonin reuptake (SISR). These effects are not mediated only in the CNS, but also in sites outside the brain, such as the intestine, which possess this type of receptors also. These receptors are not located in the platelets.

    5HT 4-7 serotonergic receptors . These receptors are distributed throughout the body, where they stimulate the alimentary tract secretions and facilitate peristaltic reflexes. Their localization in serotonergic areas in the brain and platelets has not been established.

    Notwhithstanding their limitations, the characteristics reviewed support the conclusion that platelets can be used as partial models to study the neuronal serotonin 5-HT2 binding and uptake functions. As Alfred Pletscher stated: "although the incomplete of the pattern demands care in its application, they could have the advantage of the relative simplicity".