Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus

Abstract

The suprachiasmatic nucleus (SCN) controls the circadian rhythm of physiological and behavioural processes in mammals. Here we show that prokineticin 2 (PK2), a cysteine-rich secreted protein, functions as an output molecule from the SCN circadian clock. PK2 messenger RNA is rhythmically expressed in the SCN, and the phase of PK2 rhythm is responsive to light entrainment. Molecular and genetic studies have revealed that PK2 is a gene that is controlled by a circadian clock (clock-controlled). Receptor for PK2 (PKR2) is abundantly expressed in major target nuclei of the SCN output pathway. Inhibition of nocturnal locomotor activity in rats by intracerebroventricular delivery of recombinant PK2 during subjective night, when the endogenous PK2 mRNA level is low, further supports the hypothesis that PK2 is an output molecule that transmits behavioural circadian rhythm. The high expression of PKR2 mRNA within the SCN and the positive feedback of PK2 on its own transcription through activation of PKR2 suggest that PK2 may also function locally within the SCN to synchronize output.

Bv8, the amphibian homologue of the mammalian prokineticins, modulates ingestive behaviour in rats

“…These receptors, named prokineticin receptor 1 and 2 (PKR-1 and PKR-2), belong to the family of G-protein-coupled receptors, share approximately 85% amino-acid identity and are about 80% identical to the previously described mouse orphan receptor gpr73 (Parker et al, 2000). In mouse brain, PKR-2 mRNA is expressed in the lateral septal (LS) nucleus, paraventricular, parataenial and paracentral thalamic nuclei (PVT/PT/PC), paraventricular, dorsal medial and arcuate hypothalamic nuclei (PVH/DMH/ARC), suprachiasmatic nucleus (SCN), subfornical organ (SFO), lateral globus pallidus and amygdala (Cheng et al, 2002). In previous studies, we showed that these receptors are also expressed in rat spinal cord and dorsal root ganglia, bind Bv8 with high affinity, and, when activated by Bv8, produce [Ca þ 2 ] i transients in cultured dorsal root ganglion neurones (Negri et al, 2002).…”

“…Common structural motives in this peptide family are the amino-terminal sequence of 20 amino-acid residues and the five disulphide bonds that link the 10 cysteine residues and fold the molecules into a globular form. The distribution of mRNAs of murine Bv8-like proteins has been reported in the brain, spinal cord, gastrointestinal tract, endocrine glands and other peripheral organs of mice and rats LeCouter et al, 2001;Li et al, 2001;Melchiorri et al, 2001;Cheng et al, 2002;Masuda et al, 2002). In the brain, the main localizations of mPK-2 include the olfactory bulb, cerebral cortex (in some neurones of layer II), dorsal and ventral hippocampus, medial preoptic area of the hypothalamus, suprachiasmatic nucleus (SCN), some thalamic nuclei, Purkinje cells of cerebellum, sensory and motor nuclei of the brain stem and spinal cord.…”

“…In the brain, the main localizations of mPK-2 include the olfactory bulb, cerebral cortex (in some neurones of layer II), dorsal and ventral hippocampus, medial preoptic area of the hypothalamus, suprachiasmatic nucleus (SCN), some thalamic nuclei, Purkinje cells of cerebellum, sensory and motor nuclei of the brain stem and spinal cord. Using in situ hybridization, Cheng et al (2002) found that mPK-2 mRNA is rhythmically expressed in the SCN, according to the 24-h cycle of the circadian clock. This circadian rhythm of mPK-2 mRNA expression is severely blunted in mutant mice deficient in Clock or Cryptochrome genes.…”

The regulation of neuroendocrine function: Timing is everything

“…One candidate diffusible signal is prokineticin-2 (PK2) (Cheng et al, 2002). This protein is expressed rhythmically in the SCN, and its receptor is present in all major SCN targets (Cheng et al, 2002(Cheng et al, , 2005.…”

“…This protein is expressed rhythmically in the SCN, and its receptor is present in all major SCN targets (Cheng et al, 2002(Cheng et al, , 2005. Likewise, PK2 administration during the night (when levels are low) inhibits wheel running behavior.…”