Na v 1.7, its mutations, and the syndromes that they cause

Abstract

When many of us went to medical or graduate school, we learned that “the” voltage-dated sodium channel is responsible for electrogenesis within neurons. Now, as a result of the molecular revolution, we understand that there are at least 10 different isoforms of sodium channels, all sharing a common overall motif but with different amino acid sequences, different physiologic and pharmacologic properties, and different distributions within the nervous system.1 Some of these sodium channels are expressed in a cell-specific manner. Interestingly, spinal sensory (dorsal root ganglion [DRG]) neurons preferentially express three sodium channel isoforms known as Nav1.7, Nav1.8, and Nav1.9. Nav1.7 is present at high levels in nociceptive DRG neurons, and is also present within sympathetic ganglion neurons. Nav1.7 exhibits a biophysical property called “slow closed-state inactivation,” and it therefore produces a depolarization in response to small, slow stimuli that, in themselves, may not reach the threshold for action potential generation.2 Nav1.7 is thus poised to amplify generator potentials at the nerve endings of nociceptors, close to the trigger zone where all-or-none impulses are generated, thereby setting the gain on nociceptors so that it acts a “gatekeeper” within the peripheral pain-signaling pathway.3 In the past 3 years, three distinct clinical syndromes in humans have been shown to be caused by mutations of Nav1.7 (table). Inherited erythromelalgia (also known as erythermalgia) was the first human pain syndrome shown to be produced by a mutation of an ion channel. Patients with erythromelalgia are clinically characterized by burning pain and redness of the extremities, triggered by mild warmth (e.g., entering a warm room, exercise, putting on socks), most prominent in their distal extremities (feet, hands), and in some patients in the ears, nose, or other parts of …