The voltage-gated sodium channel (SCN) alpha subunits are large proteins with central roles in the generation of action potentials. They consist of approximately 2,000 amino acids encoded by 24-27 exons. Previous evolutionary studies have been unable to reconcile the proposed gene duplication schemes with the species distribution and molecular phylogeny of the genes. We have carefully annotated...

C oronary artery disease, heart failure, and cardiac arrhythmias are major causes of morbidity and mortality in the United States. The overall death rate for all cardiovascular diseases was 236.1 per 100 000 persons, accounting for 1 of every 3 deaths in America. Cardiac diseases can affect every age group, but prevalence is seen in patients 65 or older. For instance, heart failure incidence ap...

Hypokalemic periodic paralysis (HypoKPP) is a rare, dominantly inherited disorder of muscle that is characterized by recurrent and prolonged episodes of severe weakness. These episodes are associated with low serum K (often <3.0 mM, normally 3.5–5.5 mM), often triggered by events that lower extracellular [K] such as carbohydrate-rich meals, and result in depolarization-induced loss of excitabil...

In Saccharomyces cerevisiae, the Rho-type GTPase Cdc42 regulates polarized growth through its effectors, including the p21-activated kinases (PAKs) Ste20, Cla4 and Skm1. Previously, we demonstrated that Ste20 interacts with several proteins involved in sterol synthesis that are crucial for cell polarization. Under anaerobic conditions, sterols cannot be synthesized and need to be imported into ...

BACKGROUND In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel (SCN5A) is largely inactivated, contributing to low action potential upstroke velocity (V(max)), slow conduction, and reentry. We hypothesized that a fast inward current such as the skeletal muscle sodium channel (SkM1) operating more effectively at depolarized membrane potentials might restore fast...

In Saccharomyces cerevisiae, the Rho-type GTPase Cdc42 regulates polarized growth through its effectors, including the p21-activated kinases (PAKs) Ste20, Cla4, and Skm1. Previously, we demonstrated that Ste20 interacts with several proteins involved in sterol synthesis that are crucial for cell polarization. Under anaerobic conditions, sterols cannot be synthesized and need to be imported into...

Because of their fundamental role in generating electrical impulses in many excitable tissues, sodium channels were among the first voltage-gated ion channels to be extensively investigated. Neurons bathed in a physiological solution containing 150 mM sodium ions respond to a threshold electrical stimulus by generating an action potential, whereas such a response is abolished in a Na+-free medi...

Mutations in the gene encoding the voltage-gated sodium channel of skeletal muscle (SkM1) have been identified in a group of autosomal dominant diseases, characterized by abnormalities of the sarcolemmal excitability, that include paramyotonia congenita (PC) and hyperkalemic periodic paralysis (HYPP). We previously reported that PC mutations cause in common a slowing of inactivation in the huma...

Background: Muscle channelopathies such as paramyotonia, hyperkalemic periodic paralysis, and potassiumaggravated myotonia are caused by gain-of-function Na channel mutations. Methods: Implementation of a threedimensional radial Na magnetic resonance (MR) sequence with ultra-short echo times allowed the authors to quantify changes in the total muscular Na signal intensity. By this technique and...