Ionic Basis of Cold Receptors Acting as Thermostats

<jats:p>When temperature (T) of skin decreases stepwise, cold fibers evoke transient afferent discharges, inducing cold sensation and heat-gain responses. Hence we have proposed that cold receptors at distal ends of cold fibers are thermostats to regulate skin T against cold. Here, with patch-clamp techniques, we studied the ionic basis of cold receptors in cultured dorsal root ganglion (DRG) neurons of rats, as a model of nerve endings. Cells that increased cytosolic Ca<jats:sup>2+</jats:sup>level in response to moderate cooling were identified as neurons with cold receptors. In whole-cell current-clamp recordings of these cells, in response to cooling, cold receptors evoked a dynamic receptor potential (RP), eliciting impulses briefly. In voltage-clamp recordings (-60 mV), step cooling induced an inward cold current (<jats:italic>I</jats:italic><jats:sub>cold</jats:sub>) with inactivation, underlying the dynamic RP. Ca<jats:sup>2+</jats:sup>ions that entered into cells from extracellular side induced the inactivation. Analysis of the reversal potential implied that<jats:italic>I</jats:italic><jats:sub>cold</jats:sub>was nonselective cation current with high Ca<jats:sup>2+</jats:sup>permeability. Threshold temperatures of cooling-induced Ca<jats:sup>2+</jats:sup>response and<jats:italic>I</jats:italic><jats:sub>cold</jats:sub>were different primarily among cells. In outside-out patches, when T decreased, single nonselective cation channels became active at a critical T. This implies that a cold receptor is an ion channel and acts as the smallest thermostat. Because these thermal properties were consistent with that in cold fibers, we conclude that the same cold receptors exist at nerve endings and generate afferent impulses for cold sensation and heat-gain behaviors in response to cold.</jats:p>