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PhD Thesis: Katherine J. Burton

Dissertation Abstract:
Rhythmic Regulation of TRPV2 Trafficking by Prokineticin 2 in Circadian Clock

By Katherine J. Burton
Doctor of Philosophy in Pharmacology and Toxicology
University of California, Irvine, 2008
Professor Qun-Yong Zhou, Chair

Prokineticin 2 (PK2) is an output molecule from the suprachiasmatic nucleus (SCN) of the hypothalamus which regulates circadian locomotor behavior. PK2 and prokineticin receptor 2 (PKR2) mRNA are located in target areas involved in circadian regulation, including the dorsomedial hypothalamic nucleus (DMH) known to be an integration center for mammalian sleep-wake cycle. This dissertation examines the expression patterning in circadian-targeted brain regions and the activation of TRPV2 by PK2 signaling in the SCN. Additionally, similarities and divergence in mRNA expression of prokineticins are explored in nocturnal rodent and diurnal Rhesus monkey.

Chapter 2 examines the electrical firing in SCN and the functional properties of TRPV2 via PK2 signaling. We demonstrate that PK2 increases the spontaneous firing frequency in SCN neurons. Analyses show a colocalization of PKR2 mRNA and TRPV2 protein in the SCN, paraventricular hypothalamic nucleus (PVN) and other circadian-associated targets. Oscillation of PK2 mRNA and TRPV2 mRNA peak at subjective day and diminish during the dark hours in SCN and DMH. This cationic conductance of the TRPV2 channel occurs through a time-dependent translocation to the extracellular membrane via a PI3K-mediated pathway.

Investigation of PK2 mediation on circadian regulated behaviors has been explored in the nocturnal rodent. In mouse, PK2 and PKR2 mRNA are expressed in brain regions pertinent to circadian control. Chapter 3 focuses on the expression patterning of PK2 and PKR2 in Rhesus monkey. Primate sequence homology of PKR2 is nearly identical to that in human. We also demonstrate colocalization of PKR2 mRNA and TRPV2 protein in the Rhesus monkey, highlighting the variation of expression in DMH.

Chapter 4 examines the expression of prokineticins in Rhesus monkey hypothalamic brain sections, brainstem, spinal cord and cortex. Circadian-targeted and non-circadian pathways are discussed. Divergence in PK2 mRNA expression is seen in PVN of nocturnal mouse and Rhesus monkey. Additively, this study explores the expression of prokineticin 1 (PK1) and PKR2 mRNA in the brainstem, indicating a role for PK1 in the integration of visual cues to auditory processing, specific to diurnal primate.