El polipéptido activador de la adenilato ciclasa de la pituitaria (PACAP): actualización de conocimientos

• Autores: Diana Agudelo, Samuel Mucio Ramírez, Margarita Currás Collazo, Carolina Miller Pérez
• Localización: Salud mental, ISSN 0185-3325, Vol. 27, Nº. 2, 2004, págs. 65-69
• Idioma: español
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• Resumen
  • español

    Después del descubrimiento de los factores hipotalámicos hipofisiotróficos, como el factor liberador de la hormona luteinizante, de la tirotrófica, de la hormona del crecimiento y de la corticotrofina, se caracterizaron los factores liberadores de la hormona folículo estimulante y de la hormona prolactina. Sin embargo, algunos estudios mostraron que había células no descritas, que supuestamente requerían un factor hipotalámico. Lo anterior llevó a pensar en la existencia de un nuevo factor hipofisiotrófico, lo que a su vez condujo al descubrimiento del polipéptido activador de la adenilatociclasa de la pituitaria (PACAP) por Miyata y colaboradores en 1998. Su nombre proviene del efecto que ejerce sobre las células de la pituitaria, ya que incrementa los niveles de AMP cíclico (AMPc) y causa la liberación de diferentes hormonas hipofisiarias. Como este péptido tiene una amplia distribución anatómica y participa en diversas funciones cerebrales, se despertó el interés de varios grupos de investigación por estudiar los efectos farmacológicos y las funciones biológicas en las que el PACAP participa. En esta revisión se presenta la información más reciente de las múltiples acciones fisiológicas que tiene el PACAP y sus receptores en el Sistema Nervioso Central (SNC)y en otros sistemas.

    El PACAP es un péptido de 38 aminoácidos, aislado de extractos de hipotálamo de oveja. El PACAP es miembro de la superfamilia secretina/hormona de crecimiento/glucagon/péptido intestinal vaso activo, y su secuencia es la más conservada filogenéticamente. Existen dos formas biológicamente activas del PACAP: una de 38 aminoácidos y otra truncada de 27;los dos péptidos están amidados en su extremo carboxilo terminal. El PACAP comparte una gran homología estructural con todos los péptidos pertenecientes a esta familia, principalmente con el péptido intestinal vasoactivo (VIP) de porcino, con el que muestra 68% de homología en su porción aminoterminal 1-28.La clonación molecular del ADN complementario (cDNA) del precursor del PACAP-38 de rata, ratón, bovino y humano, mostró que la secuencia de aminoácidos es 100% idéntica entre ellos. La secuencia del PACAP se identificó en diferentes especies de vertebrados y de algunos invertebrados, como los tunicados, y en anélidos. El PACAP de estas especies muestra un alto grado de identidad con el PACAP del humano con una diferencia de uno a cuatro aminoácidos. Este patrón de conservación en la secuencia de aminoácidos en las diferentes especies animales muestra la importancia biológica de este neuropéptido. Entre las funciones más relevantes del PACAP están las de ser un factor hipofisiotrófico y un neuromodulador. Los receptores para el PACAP pertenecen a la familia de los receptores acoplados a proteínas Gs que tienen siete asas transmembranales. El PACAP produce sus efectos biológicos al unirse con al menos tres tipos de receptores: los PAC-1, VPAC1 y VPAC2. El receptor PAC-1 tiene más afinidad de unión con el PACAP-38 (Kd=0.5 nM) y el PACAP-27 (Kd=2.0 nM). Los estudios de la distribución anatómica de los mRNA que codifican para el PACAP y sus receptores demuestran que se expresan desde las primeras etapas embrionarias en el ratón. El PACAP se distribuye ampliamente en el Sistema Nervioso Central, en el Sistema Nervioso Periférico y en las gónadas. En el SNC de la rata adulta se encontraron células y fibras inmunorreactivas a PACAP-38 y PACAP-27, distribuidas en la corteza cerebelar, hipocampo, septum, tálamo, núcleos supraóptico y paraventricular del hipotálamo, eminencia media, tallo cerebral y médula espinal. En testículos de rata y ratón se encontró una alta concentración de PACAP.

    Otros tejidos y órganos con células y fibras positivas a PACAP son las glándulas hipófisis, adrenales, pineal y salivales, así como el tracto gastrointestinal, el páncreas, la retina, y algunos ganglios simpáticos. El PACAP cumple con los criterios para considerarlo un factor hipofisiotrófico, ya que está presente en neuronas hipotalámicas que proyectan al sistema portahipofisiario. Asimismo, en la sangre portahipofisiaria interactúa con receptores específicos localizados en las células de la hipófisis y los regula.

  • English

    After the discovery of the hypophysiotropic hypothalamic, factors such as the luteinizing hormone releasing factor, thyrotropin hormone, growth hormone and corticotropin, the releasing factors for the follicle stimulating hormone and that of prolactin were characterized. However, some studies showed that few new cells in adenohypophysis would presumably require their hypothalamic regulator. This opened the possibility for the existence of a new hypophysiotropic factor. Eventually in 1998, a pituitary adenylate cyclase activating polypeptide (PACAP) was discovered by Miyata et al. Its name arises from the effect it exerts on pituitary cells by increasing cyclic AMP (cAMP) levels, and consequently originating the release of various hypophysial hormones, i.e., prolactin, oxytocin, vasopressin and growth hormone, among others. It has been reported that PACAP regulates important biological functions in vertebrates, being among the most relevant its role as a hypophysiotropic factor and neuromodulator. Furthermore, PACAP produced vasodilation, bronchodilation, activation of intestinal motility, increase of insulin and histamine secretion, as well as stimulation of cell multiplication and/or differentiation. This review paper provides the most recent information on the diverse physiological roles that PACAP and its receptors exert on the Central Nervous System (CNS) and on other systems. The wide anatomical distribution of this polypeptide and that of its receptors has drawn the interest of various research groups in trying to elucidate the pharmacological effects and biological functions in which PACAP participates. This peptide consists of 38 amino acids and was isolated from ovine hypothalamic extracts. Two biologically active forms exist: one having 38 residues and a truncated one of 27 residues. Both peptides are amidated in their carboxyl terminal. It is widely distributed in SNC, Peripheral Nervous System and in cells of various tissues and organs of different animal species. PACAP belongs to the superfamily secretin/growth hormone (GH)/glucagon/vasoactive intestinal polypeptide (VIP), and from a phylogenetic point of view, it has the most preserved sequence. PACAP shares a highly structural homology with all the peptides belonging to this family, mainly with porcine VIP, showing a 68% homology in its amino terminal portion. The molecular cloning of the complementary DNA of the PACAP-38 precursor of rat, mouse and human showed that the amino acid sequence was 100% identical for all of them. The PACAP sequence has been identified in different vertebrate species and in some invertebrates such as tunicates and annelids. PACAP from these species shows a high degree of identity with human PACAP, the only difference lying in one- to four-amino acids. This amino acid conservation pattern in the various animal species shows the biologic relevance of this neuropeptide. Phylogenetic evidence suggest that the PACAP gene originated from the duplication of an ancestral common gene of the superfamily secretin/GH/glucagon/VIP. Therefore, the general organization of the PACAP gene holds a great similitude with that of VIP and the rest of the members of this superfamily. In 1992 Hosoya et al. cloned the human PACAP gene, which is located in region p11 of chromosome 18. It is formed by 5 exons and 4 introns. Exon 1 codifies a cryptic protein; exon 2, the signal peptide; exon 3, a spacing protein having no apparent function; exon 4 codifies the so-called PRP peptide with no known biological function, and exon 5 codifies PACAP-38. Several groups have cloned the PACAP receptor and its isoforms. Receptors for PACAP belong to a family of receptors coupled to G proteins having 7 transmembranal domains. PACAP produces its biological effects by binding to at least 3 types of receptors PAC-1, VPAC1 and VPAC2. Receptor PAC-1 has the highest binding affinity for PACAP-38 (Kd 0.5 nM) and to a lesser degree for PACAP-27 (Kd 2.0 nM). PACAP is widely distributed in the CNS, peripheral nervous system, and various glands and organs. Anatomical studies showing the distribution of mRNA encoding PACAP and its receptors reported that this neuropeptide and corresponding receptors are expressed very early in mouse embryonic stages. Studies carried out in the CNS of adult rat reported PACAP-38 and PACAP-27 immunoreactive (IR) cells and fibers in cerebellar cortex, hippocampus, septum, thalamus, supraoptic and paraventricular hypothalamic nuclei, median eminence, medulla oblongata and spinal cord. The highest PACAP concentration outside the CNS lies in the testicles of rat and mouse. Other tissues and organs presenting IR cells and fibers are the gastrointestinal tract, pancreas, retina and some sympathetic ganglia, as well as the following glands: hypophysis, adrenal, pineal and salivary. PACAP fulfills the criteria for being considered a hypophysiotropic factor, since it is present in hypothalamic neurons projecting to the pituitary-portal system; and in the blood circulating in this system, it interacts with specific receptors localized in pituitary cells and regulates them. PACAP stimulates the synthesis and release of LH and FSH in gonadotropic cells. It also stimulates the somadendritic release of oxytocin and vasopressin. In addition, our group demonstrated that PACAP administration enhances 2 to 9 times vasopressin basal release in hypothalamic and hypophyseal slices in vitro. PACAP stimulates melanotropes by increasing POMC genomic expression, and translates its signal through cAMP and inositol phosphate pathways. PACAP increases in a dose dependent manner ±-MSH and ACTH secretions, at 1nM concentrations. PACAP also modulates prolactin release. In neocortical culture cells, it also stimulates the genomic expression of proenkephalin, which is the precursor of leu- and met-enkephalin. This polypeptide co-localizes with various neurotransmitters and/or neuromodulators in neurons, modulating their release or interacting as a whole to regulate a certain function. Among the most widely studied of these substances one may mention catecholamines, melatonin, histamine, serotonin and nitric oxide (NO). PACAP regulates the activity of male and female gonads. It stimulates testosterone secretion in Leydig cells in a dose dependent manner. In Leydig cells, PACAP activates adenylate cyclase and phospholipase C by interacting with receptor PAC-1. PACAP stimulates estradiol and progesterone secretions in the ovary of the rat. These studies and the presence of PAC-1 receptor in the granulosa cells suggest that PACAP may be an autocrine or paracrine regulator of ovarian function. PACAP activates Ca2+ channels, and as a consequence a higher catecholamine release ensues. Similarly, aldosterone secretion is increased; this mineralocorticoid regulates the electrolytic balance via a paracrine mechanism which stimulates the cells in the adrenal cortex. Likewise, it also raises cortisol levels. These findings identify PACAP as a possible adrenal gland neuromodulator in different animal species, and support the hypothesis that PACAP is an important modulator participating in functions related to the hypothalamus-hypophysis-adrenal system. PACAP diminishes nitric oxide production in a dosedependent manner in PC12 cultured cells, probably by the phosphorilation of the enzyme nitric oxide synthase, thus suggesting a regulatory role for PACAP in the activity of this enzyme. This peptide has been considered a neuroprotective factor, since it protects cortical cells and PC12 cells from glutamate cytotoxic effects. During development, PACAP acts as a neurotrophic factor, while in adult brain it acts rather as a neuroprotective agent. From what has been previously mentioned, PACAP regulates various relevant biological functions in vertebrates. Still, there are many things waiting to be elucidated with regard to this polypeptide. In this review paper we tried to include the most recent information on the participation of this peptide in diverse physiological actions.