Overexpression of the human VPAC(2) receptor in the suprachiasmatic nucleus alters the circadian phenotype of mice

S B Shen, C Spratt, W J Sheward, I Kallo, K West, C F Morrison, C W Coen, H M Marston, A J Harmar

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) belong to a superfamily of structurally related peptide hormones that includes glucagon. glucagon-like peptides, secretin. and growth hormone-releasing hormone. Microinjection of VIP or PACAP into the rodent suprachiasmatic: nucleus (SCN) phase shifts the circadian pace-maker and VIP antagonists, and antisense oligodeoxynucleotides have been shown to disrupt circadian function. VIP and PACAP have equal potency as agonists of the VPAC(2) receptor (VPAC(2)R), which is expressed abundantly in the SCN, in a circadian manner. To determine whether manipulating the level of expression of the VPAC2R can influence the control of the circadian clock, we have created transgenic mice overexpressing the human VPAC(2)R gene from a yeast artificial chromosome (YAC) construct. The YAC was modified by a strategy using homologous recombination to introduce (i) the HA epitope tag sequence (from influenza virus hemagglutinin) at the carboxyl terminus of the VPAC(2)R protein, (ii) the lacZ reporter gene, and (iii) a conditional centromere, enabling YAC DNA to be amplified in culture in the presence of galactose. High levels of lac(2) expression were detected in the SCN, habenula, pancreas, and testis of the transgenic mice, with lower levels in the of factory bulb and various hypothalamic areas. Transgenic mice resynchronized more quickly than wild-type controls to an advance of 8 h in the light-dark (LD) cycle and exhibited a significantly shorter circadian period in constant darkness (DD), These data suggest that the VPAC(2)R can influence the rhythmicity and photic entrainment of the circadian clock.

Original languageEnglish
Pages (from-to)11575-11580
Number of pages6
JournalProceedings of the National Academy of Sciences (PNAS)
Issue number21
Publication statusPublished - 10 Oct 2000


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