(9), and Ca 2ϩ influx into lymphocytes (10). 5-HT 3 receptor activation mediates emetic and inflammatory responses (11) and may contribute to pain reception, anxiety, cognition, cranial motor neuron activity, modulation of affect, and the behavioral consequences of drug abuse (Refs. 12 and 13; but see Ref. 14).The 5-HT 3A receptor subunit shares structural similarities with members of the superfamily of ligand-gated ion channels (15) and is thought to be a pentameric protein (16, 17) with multiple agonist and allosteric ligand binding sites (2, 11). Both native and recombinant 5-HT 3 receptors reveal rapid and cooperative activation by agonists and desensitization to prolonged application of 5-HT (reviewed in Refs. 1, 2, and 6). With a few exceptions, ligand-gated channels require the association of more than one kind of homologous subunit for function, and subunit composition determines the pharmacological (18) and kinetic (e.g. desensitization (19,20)) profile of heteromeric receptors. While the 5-HT 3A subunit expressed in heterologous systems functions efficiently as homomers, different voltagedependence, desensitization, and pharmacological properties between recombinant and native 5-HT 3 receptors suggest that native 5-HT 3 receptors may exist as heteromers (3,(21)(22)(23)(24)(25)(26)(27). Although the 5-HT 3A gene encodes splice variants in mouse (28, 29) and guinea pig (30), most of the characteristics of these variants are similar (29,31,32), and the subtle pharmacological differences (22, 31, 32) cannot completely account for the differences observed between recombinant homomers and native 5-HT 3 receptors. In fact, co-expression of both splice variants in oocytes could not reproduce the responses observed in the cell line from which the splice variants were cloned (22). Biochemical studies on porcine brain have revealed the existence of at least four proteins (52-71 kDa) closely associated with the 5-HT 3A subunit that may represent antigenically distinct channel subunits (33).The cloning of a 5-HT 3B subunit that modified the pharmacological and single channel characteristics of the 5-HT 3A subunit when co-expressed in heterologous expression systems was recently reported (34). We extend this report and provide evidence for the co-existence of both 5-HT 3B and 5-HT 3A receptor subunits in native cells, a requirement for heteromeric association. We show that 5-HT 3B has no effect on the function of ␣22, ␣34, ␣42, and ␣7 nicotinic ACh receptors. Furthermore, the characterization of the pharmacology and function of heteromeric receptors in Xenopus oocyte and mammalian expression systems reported here differs from that described (34), and these differences have important consequences for the function of heteromers in vivo.* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.The nucleotide sequence (s) 1 The abbreviations used...
A recently identified neuropeptide with PRL-releasing capabilities binds to and activates a previously known orphan G protein-coupled receptor, GPR10. We initiated a study to define the pharmacology of the peptide/receptor interaction and to identify the distribution of the peptide and its receptor in the central nervous system to elucidate sites of action of the peptide. The PRL-releasing peptide (PrRP) is a C-terminally amidated, 31-amino acid peptide derived from a 98-amino acid precursor. Radioiodinated PrRP-(1-31) binds to its receptor with high affinity (1 nM) and stimulates calcium mobilization in CHOK1 cells stably transfected with the receptor. A series of N-terminal deletions reveals that the PrRP-(12-31) amino acid is equipotent to PrRP-(1-31). Further N-terminal deletions reduce the affinity of the ligand considerably, although PrRP-(25-31) is still able to compete for binding and behaves as an agonist. The arginine residues at position 26 and 30 are critical for binding, as substitution with either lysine or citrulline reduces the affinity substantially. In situ hybridization reveals a distinct tissue distribution for both the peptide and receptor messenger RNAs. The receptor is expressed abundantly in the reticular thalamic nucleus, periventricular hypothalamus, dorsomedial hypothalamus, nucleus of the solitary tract, area postrema, anterior pituitary, and adrenal medulla. The peptide messenger RNA is expressed in the dorsomedial hypothalamus, nucleus of the solitary tract, ventrolateral reticular nucleus, and intestine. This tissue distribution suggests an alternative function of PrRP than its purported hypophysiotropic function, such as a potential role for PrRP in the central feedback control of neuroendocrine and autonomic homeostasis. Further work using selective agonists and antagonists should help define additional physiological roles of this novel mammalian neuropeptide.
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