The elusive Nav1.7: From pain to cancer.

Abstract

Voltage-gated sodium channels (Na_v) are protein complexes that play fundamental roles in the transmission of signals in the nervous system, at the neuromuscular junction and in the heart. They are mainly present in excitable cells where they are responsible for triggering action potentials. Dysfunctions in Na_v ion conduction give rise to a wide range of conditions, including neurological disorders, hypertension, arrhythmia, pain and cancer. Na_v family 1 is composed of nine members, named numerically from 1 to 9. A Nax family also exists and is involved in body-fluid homeostasis. Of particular interest is Na_v1.7 which is highly expressed in the sensory neurons of the dorsal root ganglions, where it is involved in the propagation of pain sensation. Gain-of-function mutations in Na_v1.7 cause pathologies associated with increased pain sensitivity, while loss-of-function mutations cause reduced sensitivity to pain. The last decade has seen considerable effort in developing highly specific Na_v1.7 blockers as pain medications, nonetheless, sufficient efficacy has yet to be achieved. Evidence is now conclusively showing that Na_vs are also present in many types of cancer cells, where they are involved in cell migration and invasiveness. Na_v1.7 is anomalously expressed in endometrial, ovarian and lung cancers. Na_v1.7 is also involved in Chemotherapy Induced Peripheral Neuropathy (CIPN). We propose that the knowledge and tools developed to study the role of Na_v1.7 in pain can be exploited to develop novel cancer therapies. In this chapter, we illustrate the various aspects of Na_v1.7 function in pain, cancer and CIPN, and outline therapeutic approaches.