2023 journal article
A new role of TRPM8 in circadian rhythm and molecular clock
Acta Physiologica.
MeSH headings : Circadian Rhythm; Circadian Clocks
TL;DR:
Evidence is provided that TRPM8 might regulate Period 2 (Per2) mRNA levels in central clock (SCN) and peripheral clock (liver and white adipose tissue) and the circadian regulation of core body temperature and the most significant advances in the field of circadian regulation using cold sensors are provided.
(via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being
(Web of Science)
Source: ORCID
Added: January 21, 2023
Over the past decades, studies of the TRPM8 channel, a nonselective cation channel, have provided much insight into the fundamental mechanisms of sensory neuron function that lead to the detection of cold sensors. In the current issue of Acta Physiologica, Reimundez et al1 provide evidence of a novel role of TRPM8 in circadian function in mice. The TRPM (transient receptor potential ion channels, where “m” stands for melastatin) is a family of eight different channels, TRPM1TRPM8.2 The TRPM8 is a cold sensor and is also activated by chemical ligands such as menthol and icilin, but recently, their role in maintaining core body temperature has also been recognized.3,4 TRPM8 is expressed in sensory neurons whose axonal afferents innervate peripheral tissues such as skin and oral cavity. Still, it has not been detected in the brain and spinal cord. Besides nerve tissues, TRPM8 is expressed in tissues such as the prostate, bladder, lungs, and urogenital tract. However, other than the sensory nervous system, the functional role of TRPM8 channels is not well understood. In this issue of Acta Physiologica, Reimundez et al1 provide solid experimental evidence for such a novel mechanism— where they demonstrate that TRPM8 might regulate Period 2 (Per2) mRNA levels in central clock (SCN) and peripheral clock (liver and white adipose tissue) and the circadian regulation of core body temperature. Their publication is among the most significant advances in the field of circadian regulation using cold sensors— it will probably set up the stage for several future research activities in which Reimundez and colleagues' ideas will be rigorously dissected and probed in circadian biology research. Previously, Ordás et al5 demonstrated the presence of TRPM8 fibers in the suprachiasmatic nucleus of the hypothalamus (SCN) of the brain, which is the principal circadian pacemaker in mammals and host a range of other physiological processes such as circadian oscillation, autonomic/peripheral and central nervous system function, regulating core body temperature and sleep– wake cycle. Since SCN receives axonal projections mainly from intrinsically photosensitive retinal ganglion cells (ipRGCs) that are responsible for resetting the circadian clock through SCN neuron activity with light as a primary zeitgeber.6 Here, authors used conventional PCR and mouse reporter lines to show the expression of TRPM8 in the inner retina, specifically in the ganglion cell layer (GC) and in the inner nuclear layer (INL). Next, they used the colocalization technique to demonstrate that melanopsin, a marker of ipRGCs7 and using mouse reporter lines, that TRPM8 expressing cells are indeed expressed in a subset of ipRGCs cells. Furthermore, they showed that TRPM8 is also expressed in cholinergic amacrine cells, characterized by releasing two neurotransmitters, GABA and acetylcholine. Injection of the fluorescent anterograde tracer cholera toxin subunit B (CTB594) into both eyes in two TRPM8 reporter lines indicates the existence of ipRGCs expressing TRPM8 and projecting to the SCN (Figure 1). The choroid is an essential high blood flow vascular structure in the eye and is known to regulate ocular and retinal temperature8 and is richly innervated by sensory trigeminal nerve fibers; therefore, the authors next examined the role of TRPM8 in regulation of eye temperature (Teye) using infrared (IR) thermography. Interestingly, they discovered mice lacking TRPM8 started to decline at temperatures below 25°C, and Trpm8−/− mice displayed a significantly lower Teye than WT littermates when the temperature plate was around 15°C. This suggests a function of TRPM8 and ambient temperature in regulating choroid and ciliary body blood flow and, therefore, in controlling internal ocular temperature. The ability of mice to regulate homeostatic temperature control and the expression of TRPM8 in the ipRGCs is indicative but does not directly link that to central clock regulation. The authors performed expression and functional studies to investigate a direct link between TRPM8 and circadian clockwork at the SCN. First, they determined the expression of the Per2 gene, which is one of the essential components of core circadian clocks in the SCN.9 Authors found in the TRPM8 deficient mouse SCN a significant