Yasuharu Kimura

Inactivation of a Novel Neuropeptide Y/Peptide YY Receptor Gene in Primate Species

Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) belong to a family of structurally related peptides which have numerous functions in both neural and endocrine signaling. By homology screening, we cloned a novel gene sharing the highest homology with the NPY Y1 receptor gene from humans, rabbits, and several other species. This novel gene of rabbit encodes a functional NPY/PYY receptor, designated Y2b, which prefers NPY13-36 rather than [Leu31,Pro34]NPY despite its higher identity with the Y1 receptor. Although, at low levels, mRNA was detected in the tissues and brain regions, including hypothalamus. Further, sequence data revealed that this gene is the orthologue of the recently cloned mouse novel NPY receptor, Y5. However, our study demonstrates that the receptor function of this gene has been inactivated in primates by a frameshift mutation occurring early in primate evolution. This novel NPY receptor represents the first neurotransmitter receptor identified that has universally lost its receptor function in primate species. Interestingly, despite its inactivation in humans, the transcripts were abundantly detected in the heart and skeletal muscle, suggesting a novel function of the human gene.

5-HT2C receptor activation is a common mechanism on proerectile effects of apomorphine, oxytocin and melanotan-II in rats

5-Hydroxytryptamine (5-HT), dopamine, oxytocin and melanocortin pathways are known to be involved in the induction of penile erections in rats. Although a dopamine-oxytocin-5-HT link in the central nervous system has been suggested to be important to the control of penile erections, the 5-HT receptor subtype that mediates dopamine-oxytocin-5-HT action and the relationship between the dopamine-oxytocin-5-HT pathway and melanocortin pathway have not been fully elucidated. In this study, in order to clarify these matters, we examined the effects of a selective 5-HT(2B)/5-HT(2C) receptors antagonist, 1-(1-methylindol-5-yl)-3-(3-pyridyl)urea (SB200646) and a selective 5-HT(2C) receptor antagonist, 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline (SB242084) on penile erections induced by a dopamine receptor agonist, 10, 11-dihydroxyaporphine (apomorphine), oxytocin, or a melanocortin receptor agonist, melanotan-II (MT-II) in rats. SB200646 at 10 mg/kg and SB242084 at 3 mg/kg, these doses which completely antagonize penile erections induced by 5-HT(2C) receptor agonists, m-chlorophenylpiperazine (mCPP) and (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348), significantly inhibited penile erections elicited by apomorphine, oxytocin or MT-II. In addition, in order to clarify further the suggestion that the 5-HT pathway projecting from medulla oblongata to lumbosacral spinal site and lumbosacral 5-HT(2C) receptor are involved in the induction of penile erection, we also examined the proerectile effect of YM348 in spinal and a 5-HT depletor, p-chlorophenyl alanine (pCPA)-treated rats. YM348 induced intracavernous pressure increase in spinal and pCPA-treated rats as well as normal rats. These results suggest that 5-HT(2C) receptor in lumbosacral spinal sites mediates not only dopamine-oxytocin-5-HT action but melanocortin action on penile erections, and that the 5-HT pathway is located downstream from melanocortin pathway as well as the dopamine-oxytocin pathway.

Supraspinal influence on intracavernous pressure increase by subcutaneous injections of MCPP

554 ABNORMAL NEURAL INPUTS FROM THE MEDIAN PREOPTIC NUCLEUS TO THE HYPOTHALAMIC PARAVENTJUCULAR NUCLEUS IN SPONTANEOUSLY HYPERTENSIVE RATS JUNICHI TANAKA’, YASUSHI HAYASHI 2, KATSUHIDE KARIYA3, MASAHIKO NOMURA4 Depts. of ‘Human Dev. and 2Educ. for Handicapped Child., Naruto Univ. of Educ., Naruto, Tokushima 772-8502, 3Res. Lab., Torii & Co. Ltd., Midori-ku, Chiba 267-0056, 4Dept. of Physiol., Saitama Med. Sch., lruma-gun, Saitama, 350-0495 Extracellular single-unit activity was recorded from phasically firmg neurohypophyseal neurons tn the hypothalamic paraventricularnucleus (PVN) of male Wistar-Kyoto (WKY, 40 units) and spontaneously hypertensive rats (SHR, 38 units) under urethane anesthesia. Electrical stimulation of the median preoptic nucleus (MnPO) J)roduced orthodromic excitatton (48% in WKY rats; 51% in SHR) or inhibition (10% in WKY rats; 13% in SHR) of the activity of PVN units. No signifmant differences in the latency, duration or threshold of the MnPG stimulus-induced responses were observed between WKY and SHR. The magnitude of excitatory response, but not the inhtbitory response, much greater in SHR than m WKY rats. Local administration of angiotensin II (ANG II) into the stimulation sites enhanced the neuronal activity of units (64% in WKY rats; 67% in SHR) that displayed the excitation to electrical stimulation of the MnPO. The duration and frequency of excitatory response caused by the ANG II injection was much greater in SHR than in WKY rats. These results suggest that ANG IIsensitive MnPO efferents to the PVN act to facilitate the excitability of putative vasopressin-secreting neurons in the PVN and imply that there is the alteration between WKY and SHR in the functron of the pathways.