Receptor guanylyl cyclase‐G is a novel thermosensory protein activated by cool temperatures

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Abstract
Transmembrane guanylyl cyclases (GCs), with activity regulated by peptide ligands and/or calcium‐binding proteins, are essential for various physiological and sensory processes. The mode of activation of the GC subtype GC‐G, which is expressed in neurons of the Grueneberg ganglion that respond to cool temperatures, has been elusive. In searching for appropriate stimuli to activate GC‐G, we found that its enzymatic activity is directly stimulated by cool temperatures. In this context, it was observed that dimerization/oligomerization of GC‐G, a process generally considered as critical for enzymatic activity of GCs, is strongly enhanced by coolness. Moreover, heterologous expression of GC‐G in cultured cells rendered these cells responsive to coolness; thus, the protein might be a sensor for cool temperatures. This concept is supported by the observation of substantially reduced coolness‐induced response of Grueneberg ganglion neurons and coolness‐evoked ultrasonic vocalization in GC‐G‐deficient mouse pups. GC‐G may be a novel thermosensory protein with functional implications for the Grueneberg ganglion, a sensory organ responding to cool temperatures. Synopsis Many membrane proteins respond to extracellular ligands, but sensory nerves use specialized sensors also to report environmental temperatures. The transmembrane receptor guanylyl cyclase subtype GC‐G, expressed in Grueneberg ganglion neurons of the murine nose, is a novel type of molecular sensor for cool ambient temperatures in mammals. GC‐G expression in mouse is confined to Grueneberg ganglion neurons of the murine nose. Cool temperature stimulates the enzymatic activity of the GC‐G guanylyl cyclase by inducing its dimerization/oligomerization. Coolness‐induced stimulation of the thermosensory GC‐G guanylyl cyclase activates the Grueneberg ganglion neurons by increasing the cGMP concentration and opening cGMP‐dependent Ca2+‐permeable channels for elevating intracellular Ca2+ levels. Independent of more classical sensors like the coolness‐activated TRPM8 ion channel, GC‐G is critical for coolness‐evoked ultrasound‐vocalization in abandoned mouse pups to elicit maternal‐care behaviors.
Funding Information
  • National Science Council (NSC‐97‐2320‐B‐001‐009‐MY3)
  • Deutsche Forschungsgemeinschaft (Br712/24‐1)
  • Bundesministerium für Forschung, Technologie und Raumfahrt (01PL11003)
  • Taiwan Mouse Clinic (NSC 102‐2325‐B‐001‐042)
  • National Research Program for Biopharmaceuticals
  • National Science Council

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