The structures of the cytosolic portion of voltage activated sodium channels (CTNav) in complexes with calmodulin and other effectors in the presence and the absence of calcium provide information about the mechanisms by which these effectors regulate channel activity. The most studied of these complexes, those of Nav1.2 and Nav1.5, show details of the conformations and the specific contacts th...

There are nine recognized members of the voltage-gated Na+ channel family (VGSC; Nav1.1Nav1.9). Of these, Nav1.1, Nav1.2, Nav1.3 and Nav1.6 are highly (but not exclusively) expressed in the central nervous system (CNS), whereas Nav1.7, Nav1.8 and Nav1.9 demonstrate a more restricted expression pattern in autonomic and sensory neurons of the peripheral nervous system (PNS). Nav1.4 and Nav1.5 rep...

Hille (1977. Journal of General Physiology. 69:497-515) first proposed a modulated receptor hypothesis (MRH) to explain the action of benzocaine in voltage-gated Na+ channels. Using the MRH as a framework, we examined benzocaine binding in batrachotoxin (BTX)-modified Na+ channels under voltage-clamp conditions using either step or ramp command signals. We found that benzocaine binding is stron...

Voltage-gated Na+ channels are major targets of G protein-coupled receptor (GPCR)-initiated signaling cascades. These cascades act principally through protein kinase-mediated phosphorylation of the channel alpha subunit. Phosphorylation reduces Na+ channel availability in most instances without producing major alterations of fast channel gating. The nature of this change in availability is poor...

Local anesthetics bind to ion channels in a state-dependent manner. For noninactivating voltage-gated K channels the binding mainly occurs in the open state, while for voltage-gated inactivating Na channels it is assumed to occur mainly in inactivated states, leading to an allosterically caused increase in the inactivation probability, reflected in a negative shift of the steady-state inactivat...

The mechanisms of action of many CNS drugs have been studied extensively on the level of their target proteins, but the effects of these compounds on the level of complex CNS networks that are composed of different types of excitatory and inhibitory neurons are not well understood. Many currently used anticonvulsant drugs are known to exert potent use-dependent blocking effects on voltage-gated...

Sudden exposure of dissociated hippocampal neurons to strongly hypoor hyperosmotic solutions suppresses voltage gated Na +, K + and Ca 2+ currents. We investigated whether ligand gated ion currents were similarly shut down by exposure to anisosmotic solutions. The effect of hypo-osmotic, NaCI deficient (mannitol-substituted), or hyper-osmotic test solutions delivered from a flow pipette was tes...

Sudden exposure of dissociated hippocampal neurons to strongly hypo- or hyperosmotic solutions suppresses voltage gated Na+, K+ and Ca2+ currents. We investigated whether ligand gated ion currents were similarly shut down by exposure to anisosmotic solutions. The effect of hypo-osmotic, NaCl deficient (mannitol-substituted), or hyper-osmotic test solutions delivered from a flow pipette was test...

1. Two recently identified channel types in Lymnaea stagnalis heart muscle cells were shown to conduct Na+ in the absence of extracellular Ca2+. They did not appear to be 'voltage-gated' as they were not activated by voltage. Also, they remained active over a wide range of membrane potentials. However, they were weakly 'voltage-sensitive' as their activity usually tended to increase with depola...

Voltage-gated Na channels in several classes of neurons, including cells of the cerebellum, are subject to an open-channel block and unblock by an endogenous protein. The Na(V)beta4 (Scn4b) subunit is a candidate blocking protein because a free peptide from its cytoplasmic tail, the beta4 peptide, can block open Na channels and induce resurgent current as channels unblock upon repolarization. I...