Abstract
The mammalian circadian clock is composed of single-cell oscillators. Neurochemical and electrical signaling among these oscillators is important for the normal expression of circadian rhythms. Prokineticin 2 (PK2), encoding a cysteine-rich secreted protein, has been shown to be a critical signaling molecule for the regulation of circadian rhythms. PK2 expression in the suprachiasmatic nucleus (SCN) is highly rhythmic, peaking during the day and being essentially absent during the night. Mice with disrupted PK2 gene or its receptor PKR2 display greatly reduced rhythmicity of broad circadian parameters such as locomotor activity, body temperature and sleep/wake patterns. PK2 has been shown to increase the firing rate of SCN neurons, with unknown molecular mechanisms. Here we report that TRPV2, an ion channel belonging to the family of TRP, is co-expressed with PKR2 in the SCN neurons. Further, TRPV2 protein, but not TRPV2 mRNA, was shown to oscillate in the SCN in a PK2-dependent manner. Functional studies revealed that TRPV2 enhanced signaling of PKR2 in calcium mobilization or ion current conductance, likely via the increased trafficking of TRPV2 to the cell surface. Taken together, these results indicate that TRPV2 is likely part of the downstream signaling of PK2 in the regulation of the circadian rhythms.
Highlights
The suprachiasmatic nucleus (SCN) of the hypothalamus houses the master circadian pacemaker in mammals [1]
As PKR2 is coexpressed with TRPV2 in the SCN neurons, we examined whether the circadian oscillation of TRPV2 is linked to Prokineticin 2 (PK2) signaling with PK2-deficient (PK2-/-) mice
The coexpression of PKR2 and TRPV2 in the SCN neurons was demonstrated by combined in situ hybridization and immunostaining (Fig. 1)
Summary
The suprachiasmatic nucleus (SCN) of the hypothalamus houses the master circadian pacemaker in mammals [1]. The SCN is composed of many single-cell oscillators that, when synchronized, produce a coordinated circadian output [3, 4, 5]. One prominent feature of SCN neurons is the circadian oscillation of their firing rate, which peaks during the light phase [5]. Genetic studies in flies have revealed the critical role of firing rate oscillation in the generation of circadian rhythm [6]. Neurochemical and electrical signaling among SCN neurons is necessary for these individual cellular clocks to coordinate their activities and maintain robust oscillations [3, 4, 7, 8, 9]
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