Probing the Contribution of Nav1.7 and Nav1.8 to Cold Tolerance in Hibernators

Abstract

Voltage-gated sodium (Nav) channels play an important role in the transduction of sensory signals. Nav1.7 and Nav1.8 are primarily expressed in peripheral sensory neurons, particularly small diameter nociceptors and temperature sensors. Mutations that alter the functional properties of these channels cause severe pain disorders or pain insensitivity in humans.Small depolarizations of the neuronal membrane caused by sensory receptor channels activate Nav channels, which further depolarize the sensory neuron and generate action potentials. Here, we test this general paradigm with regard to cold sensitivity using a model organism that is tolerant to cold. Thirteen-lined ground squirrels (Ictidomys tridecemlineatus ) are able to tolerate very low temperatures during hibernation, but also show resistance to cold in the active state. Electrophysiological recordings of dissociated sensory neurons from active squirrels reveal that both Nav1.7 and Nav1.8 activity is suppressed at cold temperatures. The suppression is manifested as a shift in activation voltage-dependence and a reduction of current density. We propose that these changes regulate neuronal firing in response to cold and thus contribute to a mechanism for cold tolerance. Our results suggest a molecular model of cold resistance at the level of primary afferents.