Asthma is characterized by airway inflammation, airway wall remodelling and bronchial hyperresponsiveness. Generally it is agreed that contractions of airway smooth muscle cells (ASMC) contribute to the increased airways resistance, however the mechanisms regulating contraction are poorly understood1. ASMC possess an impressive inventory of plasmalemmal ion channels, including voltage-dependent Ca2+ channels (VDCC), large conductance Ca2+-activated K+ channels (BK), Ca2+-activated Cl- channels (ClCa) and a variety of TRP channels2. Activation of VDCC by membrane depolarization triggers an increase in intracellular Ca2+ and ASM contraction3. A series of recent papers has begun to point to the importance of voltage-dependent ion channels, in certain types of asthma. For example, polymorphisms in a regulatory γ-subunit of VDCC (CACNG6) have been associated with aspirin intolerant asthma4, while polymorphisms in the smooth muscle specific regulatory β1-subunit (KCNMB1) of BK channels are associated with asthma severity in African Americans5. L-type Ca2+ channel blockers are effective at inhibiting acute bronchospasm induced by exercise, cold air, acetylcholine, histamine and allergen stimulation6. However, a conspicuous lack of success in targeting voltage-dependent ion channels (specifically, VDCC blockers or K+ channel openers) in the treatment of chronic asthma has led to a shift of emphasis away from membrane potential-dependent regulation of contraction of airway smooth muscle (ASM), towards the role of pharmacomechanical coupling7. In chronic asthma, it appears that the Ca2+ regulatory mechanisms in ASM have been altered to render them less susceptible to agents that target Ca2+ channels and membrane potential7. However, the relationship of voltage-dependent ion channels to chronic asthma may be in the development of the condition, rather than in directly mediating its associated problems. A recent study showed that repeated bronchospasm, induced by either cholinergic or allergenic stimulation, led to airway remodelling in asthmatic patients, suggesting that therapy should be directed towards the prevention of bronchospasm in the early stages of the disease8. In the light of such findings, we decided to re-examine the role of ion channels and membrane potential in the regulation of ASMC. ASMC were isolated from rabbit bronchi using collagenase/proteinase and membrane currents recorded using the patch clamp technique. Depolarisation from negative membrane potentials evoked fast voltage-dependent Na+ currents (INa)9. As this current was large (e.g. 1-4 nA at -30 mV) and was present in the majority of cells, we were surprised to find that it had not been previously observed in freshly dispersed adult ASMC. We speculated that the experimental conditions used by others interfered with the current. For instance, papain is often used to isolate smooth muscle cells. However, INa in ASMC disappeared within 15 min of exposure to papain9. Comparison of the current in ASMC with current mediated by NaV1.5 α subunits expressed in HEK 293 cells revealed similar voltage-dependences of activation (V1/2 = -42 mV for ASMC, -49 mV for NaV1.5), inactivation (V1/2 = 88 mV for ASMC, -85 mV for NaV1.5) and sensitivities to tetrodotoxin (IC50 = 1.1 μM for ASMC and 1.2 μM for NaV1.5). These characteristics strongly suggested that INa in rabbit ASMC was mediated by NaV1.5. RT-PCR for NaV1.2-1.9 in groups of ~20 isolated ASMC, and from whole bronchial tissue, revealed that most transcripts were present in whole tissue but only NaV1.5 and 1.2 were detected in isolated ASMC. The functional significance of INa in airways is puzzling, particularly because V1/2 of inactivation ( 88 mV) implies that its availability would be negligible at normal physiological potentials. Indeed, repeated attempts to demonstrate a role in contraction of rabbit ASM have, so far, been unsuccessful. However, in preliminary experiments we have isolated ASMC from tissue obtained from human patients ungoing lung resection for carcinoma. These cells also demonstrated a TTX-sensitive INa, but it inactivated over a more depolarised range of membrane potentials (e.g. V1/2 = 43 mV) than those obtained from rabbits (Fig. 1). At present it is not clear whether INa is mediated by different molecular subunits in rabbits and humans, or if the differences are accounted for by modulation of the Na+ channels by other factors. It is conceivable that the voltage-dependent kinetics of inactivation and inactivation could be shifted under pathological conditions due to the presence of inflammatory mediators. Further work will be necessary to explore the reasons for these differences and the potential function of INa in airways.