These to date remain the only two reports
These to date remain the only two reports of mutations in GC-C found in humans. Perhaps this once again emphasized the critical requirement of the presence of an optimally functional GC-C in the intestine, since neither its loss, nor its hyperactivity, can be tolerated in humans without severe consequences. In addition, in recognition of the differences that are known between the mouse and the human immune system , it becomes important to realize that perhaps not all of the reported roles of GC-C in the mouse may be applicable in human physiology.
Future perspectives Cyclic GMP has always been considered the ‘poor cousin’ of cAMP. Nevertheless, its signaling machinery is no less sophisticated. A knock out of PKGII, the isoform predominantly expressed in the intestine, resulted in mice being resistant to ST-mediated fluid accumulation, as might be expected . However, an unexpected finding was that these mice showed skeletal abnormalities and dwarfism, indicating that cGMP and PKG II were involved in bone development , . PKGII knock-out mice were also defective in resetting the circadian clock, since PKG II activity was is required for the correct modulation of Per1 and Per2 levels . Intriguingly, guanylin and uroguanylin show circadian regulation in the rat intestine , thus suggesting a tantalizing link between the intestine, behavior and circadian rhythm. The multiple abnormalities seen in patients with altered GC-C activity or Safingol reveal an underlying complexity in the precise roles of GC-C and its ligands in mediating intestinal homeostasis. We anticipate that additional signaling outputs from GC-C may depend on its apical or basolateral localization in the epithelial cell, which could allow its association with specific signaling partners, perhaps via direct protein–protein interaction. The multi-domain nature of GC-C, and perhaps novel post-translational modifications mediated via phosphorylation, may make GC-C amenable for such interactions, as has been reported for c-src . A large fraction of GC-C is localized to the endoplasmic reticulum (ER), and glycosylated differently to the form that is found on the plasma membrane , . The precise role of this ‘intracellular’ pool of GC-C is enigmatic. Is it a fraction that is poised to be secreted to the plasma membrane in a regulated manner? Or are there specific roles for ER-localized GC-C, in that it may respond to stimuli other than its known ligands, in a cGMP-independent manner? These are some of the questions that we wish to address in the coming years. Our motivation stems primarily from recent observations indicating the somewhat serious consequences of abnormal GC-C signaling in the intestine, that suggest that much remains unknown about this receptor, its ligands and cGMP signaling in the intestinal epithelial cell.
Introduction Detection of temperature by dedicated thermosensory circuits allows animals to seek optimal thermal conditions for survival and reproduction and to avoid noxious heat or cold (Terrien et al., 2011). Although members of the conserved transient receptor potential (TRP) family of cation channels mediate thermosensation in multiple metazoans (Barbagallo and Garrity, 2015, Vriens et al., 2014), whether proteins other than TRP channels also act as thermosensors in diverse species remains to be fully determined. C. elegans acclimates to its cultivation temperature (T), and exhibits distinct thermotaxis strategies in physiological temperature ranges relative to T (Hedgecock and Russell, 1975). Behavioral acclimation to T is reflected in part by adaptation of the thermosensory response threshold () of the bilateral AFD sensory neuron pair (Biron et al., 2006, Clark et al., 2006, Kimura et al., 2004, Mori and Ohshima, 1995, Ramot et al., 2008, Yu et al., 2014). Measurements of intracellular calcium dynamics and temperature-evoked currents have shown that AFD depolarizes and hyperpolarizes upon warming and cooling, respectively, at temperatures warmer than to drive thermotaxis behaviors (Clark et al., 2006, Kimura et al., 2004, Ramot et al., 2008). Thermosensory responses and adaptation appear to be cell-intrinsic properties, although AFD response dynamics can be further shaped by surrounding glial cells (Kobayashi et al., 2016, Yoshida et al., 2015). However, despite extensive characterization of thermosensation in C. elegans, the molecular nature of thermosensor(s) in AFD remains unidentified.