Disruption of the Circadian Output Molecule Prokineticin 2 Results in Anxiolytic and Antidepressant-like Effects in Mice

Abstract

Disrupted circadian rhythms are strictly associated with mood disorders. The suprachiasmatic nucleus (SCN) is the master pacemaker that drives circadian rhythms in mammals. However, the underlying molecular connections of circadian rhythm and mood disorders are still poorly understood. Prokineticin 2 (PK2) is a signaling molecule that is critical for transmitting the circadian rhythms from the SCN. Previously, it is has been shown that the receptor for PK2 is expressed in virtually all of the primary SCN target areas, most of which are also involved in the mood regulation. In the current study, we investigated the role of PK2 in the regulation of anxiety and depressionrelated behaviors. Intracerebroventricular (ICV) infusion of PK2 increased anxiety-like behavior as assessed by light-dark box. ICV delivery of PK2 also led to increased depression-like behavior in the forced swimming test. Conversely, mice lacking the PK2 gene (PK2 À/À mice) displayed significantly reduced anxiety and depression-like behaviors. Furthermore, PK2 À/À mice showed impaired responses to new environments in terms of locomotor activity, arousal, body temperature, and food intake. Our studies, thus, indicate that PK2 signaling plays a critical role in the stress-related traits in mice, and establish a possible molecular link between circadian rhythms and mood regulation.

Possible Association of Prokineticin 2 Receptor Gene (PROKR2) with Mood Disorders in the Japanese Population

“…A recent animal study reported that PK2 gene deficit mice showed disruptions in the homeostatic regulation of sleep, such as reduced non-rapid eye movement sleep time and increased rapid eye movement (REM) sleep time in both light and dark periods (Hu et al 2007). Mice lacking the PK2 gene also showed significantly reduced anxiety and depressionlike behaviors in the forced swimming test (Li et al 2009). In addition, PK2 gene deficit mice showed deceased responses to new environments in terms of locomotor activity, arousal, body temperature, and food intake (Li et al 2009).…”

“…Mice lacking the PK2 gene also showed significantly reduced anxiety and depressionlike behaviors in the forced swimming test (Li et al 2009). In addition, PK2 gene deficit mice showed deceased responses to new environments in terms of locomotor activity, arousal, body temperature, and food intake (Li et al 2009). On the other hand, PK2 receptor, a G-coupled receptor for PK2 expressed in SCN and its targets (Cheng et al 2002), has also been shown to be essential for circadian behavior control; PK2 receptor gene mutant mice showed disrupted circadian coordination of the activity cycle and lost precision in the timing of the onset of nocturnal locomotor activity (Prosser et al 2007).…”

“…PK2 gene deficit mice showed reduced physiological and behavioral parameters, including circadian locomotor activity, circulating glucocorticoid, glucose levels, and the expression of peripheral clock genes such as Bmal1 and Dbp compared with WT mice (Li et al 2006;Li et al 2009). The expression of PK2 gene in SCN was activated by the Clock/Bmal1 complex, and suppressed by Per/Cry in vitro studies (Cheng et al 2002).…”

Role of Prokineticin in Epicardial Progenitor Cell Differentiation to Regenerate Heart

“…They also induce cell motility such as angiogenesis (LeCouter and Ferrara, 2002), neurogenesis (Ng, et al, 2005), hemotopoiesis (LeCouter, et al, 2004), neovasculogenesis (Urayama, et al, 2008). Prokineticins regulate complex behaviors such as feeding (Negri, et al, 2004), drinking (Negri, et al, 2004), anxiolity (Li, et al, 2009). Moreover, prokineticins are potent survival/mitogenic factors for various cells including endothelial cells , neuronal cells (Kisliouk, et al, 2005;Ngan, et al, 2007a), lymphocytes, hematopoietic stem cells (LeCouter, et al, 2004), and cardiomyocytes (Nebigil, 2009).…”

Disease-causing Mutation in PKR2 Receptor Reveals a Critical Role of Positive Charges in the Second Intracellular Loop for G-protein Coupling and Receptor Trafficking

“…Prokineticins are a pair of signal factors involved in a variety of physiological processes, including gastrointestinal mobility, circadian rhythms, emotion, nociception, angiogenesis, and neurogenesis (2)(3)(4)(5). Prokinticins execute their functions by binding to two closely related GPCRs, PKR1 and PKR2 (6,7).…”