Sodium channel protein type 10 subunit alpha (Nav1.8) and Sodium channel protein type 5 subunit alpha (Nav1.5) (Nav1.8/Nav1.5)

Voltage-gated sodium channels (VGSCs) are essential transmembrane proteins that facilitate the rapid influx of sodium ions, a process fundamental to the initiation and propagation of action potentials in excitable tissues. This target profile specifically addresses two distinct alpha subunits: Nav1.8 (encoded by SCN10A) and Nav1.5 (encoded by SCN5A). Nav1.8 is primarily localized in peripheral sensory neurons (nociceptors) and plays a critical role in the transmission of pain signals, making it a high-priority target for the development of non-opioid analgesics [UniProt: Q9Y5Y9, PubMed: 30104724]. In contrast, Nav1.5 is the predominant sodium channel in the heart, responsible for maintaining normal cardiac rhythm and conduction velocity [UniProt: Q14524, PubMed: 25411331]. While Nav1.8 is a therapeutic target for neuropathic and inflammatory pain, Nav1.5 is frequently considered a major safety anti-target, as unintended inhibition can lead to life-threatening cardiac arrhythmias. Modern drug discovery efforts, such as the development of suzetrigine (VX-548), focus on achieving high isoform selectivity for Nav1.8 over Nav1.5 to provide effective analgesia without cardiac or central nervous system toxicities [NEJM: 10.1056/NEJMoa2314292].

Other names

Sodium channel protein type 10 subunit alphaSodium channel protein type 5 subunit alphaSCN10ASCN5ANav1.8Nav1.5Peripheral nerve sodium channel 3 (PN3)Sensory neuron-specific sodium channel (SNS)Cardiac sodium channel alpha subunitSkM1HB1

Inhibition of sodium ion influx through the channel pore; selective Nav1.8 inhibition for analgesia; non-selective blockade of the sodium channel pore; state-dependent binding to the inactivated channel state [PubMed: 30104724, StatPearls: NBK499964].