RESUMEN
Urotensin-II (U-II) is a vasoactive 'somatostatin-like' cyclic peptide which was originally isolated from fish spinal cords, and which has recently been cloned from man. Here we describe the identification of an orphan human G-protein-coupled receptor homologous to rat GPR14 and expressed predominantly in cardiovascular tissue, which functions as a U-II receptor. Goby and human U-II bind to recombinant human GPR14 with high affinity, and the binding is functionally coupled to calcium mobilization. Human U-II is found within both vascular and cardiac tissue (including coronary atheroma) and effectively constricts isolated arteries from non-human primates. The potency of vasoconstriction of U-II is an order of magnitude greater than that of endothelin-1, making human U-II the most potent mammalian vasoconstrictor identified so far. In vivo, human U-II markedly increases total peripheral resistance in anaesthetized non-human primates, a response associated with profound cardiac contractile dysfunction. Furthermore, as U-II immunoreactivity is also found within central nervous system and endocrine tissues, it may have additional activities.
Asunto(s)
Proteínas de Unión al GTP/agonistas , Proteínas de Unión al GTP/metabolismo , Receptores de Superficie Celular/agonistas , Receptores Acoplados a Proteínas G , Urotensinas/farmacología , Vasoconstrictores/farmacología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Calcio/metabolismo , Línea Celular , Clonación Molecular , ADN Complementario , Proteínas de Unión al GTP/genética , Humanos , Macaca fascicularis , Masculino , Datos de Secuencia Molecular , Ratas , Ratas Sprague-Dawley , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Homología de Secuencia de Aminoácido , Distribución Tisular , Urotensinas/metabolismo , Vasoconstrictores/metabolismoRESUMEN
The hypothalamus plays a central role in the integrated control of feeding and energy homeostasis. We have identified two novel neuropeptides, both derived from the same precursor by proteolytic processing, that bind and activate two closely related (previously) orphan G protein-coupled receptors. These peptides, termed orexin-A and -B, have no significant structural similarities to known families of regulatory peptides. prepro-orexin mRNA and immunoreactive orexin-A are localized in neurons within and around the lateral and posterior hypothalamus in the adult rat brain. When administered centrally to rats, these peptides stimulate food consumption. prepro-orexin mRNA level is up-regulated upon fasting, suggesting a physiological role for the peptides as mediators in the central feedback mechanism that regulates feeding behavior.