Editorial Focus CALL FOR PAPERS Physiology and Pharmacology of Temperature Regulation Ion channel proteins in neuronal temperature transduction: from inferences to testable theories of deep-body thermosensitivity

THE RECENT MODEL ANALYSIS of hypothalamic neuronal thermosensitivity by Wechselberger et al. (this issue) highlights the progress made in identifying ion channels and in elucidating temperature dependencies of their properties as a new perspective for unraveling the neuronal network of temperature regulation (28). Proceeding from sequence homologies, (super-) families of genes encoding a multitude of ion channel proteins have been identified. So far, the mechanisms underlying temperature transduction by a peripheral or a central nervous system (CNS) neuron could only be inferred from the temperature coefficients of the classical triad of 1) voltage-gated, rapidly inactivating sodium and 2) delayed noninactivating potassium channels and 3) sodium-potassium ATPase (21) supplemented later by the Kv4.1 (potassium A) channel, which slows repetitive neuronal excitation and displays a Q10 1 of its inactivation rate (6). Additional immunocytochemical evidence is now presented by Wechselberger et al. (28) for the presence in hypothalamic neurons of hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels (12), accounting for inward currents at normal membrane potential and K2P (tandem-pore potassium-selective) “background” or “leak” channels (10, 13, 14, 22) acting to stabilize the resting membrane potential (17). Proceeding from the temperature dependencies of HCN channel activation and Kv4.1 channel inactivation rate, respectively, the temperature influence on conductance of K2P channel subtypes and their relative expression levels are considered in model calculations to assess their combined influence on neuronal thermoresponsiveness. Subtypes of the transient receptor potential (TRP) cation channel superfamily (5, 15), may additionally contribute to neuronal thermosensitivity, according to studies on model cells or neurons in which they are expressed. TRPV3/TRPV4 channels have positive temperature coefficients (2). The TRPM8 channel exhibits a negative temperature coefficient (20). The study by Wechselberger et al. (28) is exemplary in that it shows for CNS neurons how knowledge about the channel expression pattern of a particular neuron may be combined with results of electrophysiological channel function analysis to predict the neuron’s temperature-transducing property. However, elucidation of the roles played by the aforementioned channel proteins in peripheral temperature perception and, in particular, in neurons sensing deep-body temperature, requires observation of several preconditions. First, as documented by various references listed below, the distribution of channels is 1) ubiquitous, more or less, both in nonexcitable cells and in neurons and 2) they respond to a multitude of physical and chemical stimuli, including endogenous signal molecules. Therefore, independent evidence is required for the thermoafferent or thermointegrative function of a neuron with known temperature dependence of its activity. Second, the proportions of different membrane channel subtypes expressed in a given neuron may be critical. The above model (28) proposes, for instance, that a high-density of K2P channels with a Q10 1 would tend to hyperpolarize a CNS neuron with rising temperature, thereby stabilizing it against depolarizing temperature effects transmitted by, e.g., HCN (and/or TRPV3/ TRPV4) channels with a Q10 1 existing simultaneously. Conversely, their inactivation by decreasing temperature would enhance a neuron’s cold sensitivity in the presence of simultaneously expressed TRPM8 channels with Q10 1. To consider the other extreme, fewer and/or less temperaturedependent K2P channels, e.g., TASK-1 (28), would increase a neuron’s activation by rising temperature, if Kv 4.1, HCN, or TRPV3/TRPV4 channels are simultaneously present, whereas simultaneously present TRPM8 channels would become less effective in activating a neuron by cooling. Analysis of peripheral thermoreception has met the difficulty that the free nerve endings of skin’s cold and warm receptors are barely accessible to combined histochemical and electrophysiological analysis. Therefore, heterologous expression of channel proteins and studies on dorsal root ganglion cells expressing defined receptors are in the focus of analysis. For “cold transduction” in rat primary sensory neurons, inhibition of background potassium conductance was proposed (22). The involvement of TRPM8 channels in cold signal transduction of a cell is strongly suggested by the similarity of their responses to those of cold fibers and by their combined cold and menthol sensitivity and inactivation by calcium entry, as it has also been found in populations of cultured rat dorsal root ganglion neurons (18, 23). For innocuous heat perception, the K2P channel family may be important in view of evidence for warmth sensitivity of the TREK-1, TREK-2, and TRAAK subtypes and a lesser temperature dependence of the TASK-1 subtype (10, 13, 14, 28). Among the TRP channels, TRPV3/ TRPV4 have been implicated in transduction of touch and noxious heat. Their involvement in neuronal warmth percep-