A calcium sensor in the sodium channel modulates cardiac excitability.

Sodium channels are principal molecular determinants responsible for myocardial conduction and maintenance of the cardiac rhythm. Calcium ions (Ca2+) have a fundamental role in the coupling of cardiac myocyte excitation and contraction, yet mechanisms whereby intracellular Ca2+ may directly modulate Na channel function have yet to be identified. Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted CaM binding and eliminated Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM were restored by intracellular application of a peptide modelled after the IQ domain. A naturally occurring mutation (A1924T) in the IQ domain altered hH1 function in a manner characteristic of the Brugada arrhythmia syndrome, but at the same time inhibited slow inactivation induced by Ca2+/CaM, yielding a clinically benign (arrhythmia free) phenotype.     

A sodium-channel mutation causes isolated cardiac conduction disease

Cardiac conduction disorders slow the heart rhythm and cause disability in millions of people worldwide. Inherited mutations in SCN5A, the gene encoding the human cardiac sodium (Na+) channel, have been associated with rapid heart rhythms that occur suddenly and are life-threatening; however, a chief function of the Na+ channel is to initiate cardiac impulse conduction. Here we provide the first functional characterization of an SCN5A mutation that causes a sustained, isolated conduction defect with pathological slowing of the cardiac rhythm. By analysing the SCN5A coding region, we have identified a single mutation in five affected family members; this mutation results in the substitution of cysteine 514 for glycine (G514C) in the channel protein. Biophysical characterization of the mutant channel shows that there are abnormalities in voltage-dependent 'gating' behaviour that can be partially corrected by dexamethasone, consistent with the salutary effects of glucocorticoids on the clinical phenotype. Computational analysis predicts that the gating defects of G514C selectively slow myocardial conduction, but do not provoke the rapid cardiac arrhythmias associated previously with SCN5A mutations.     

The cosmological density of baryons from observations of 3He+ in the Milky Way.

Primordial nucleosynthesis after the Big Bang can be constrained by the abundances of the light elements and isotopes 2H, 3He, 4He and 7Li (ref. 1). The standard theory of stellar evolution predicts that 3He is also produced by solar-type stars, so its abundance is of interest not only for cosmology, but also for understanding stellar evolution and the chemical evolution of the Galaxy. The 3He abundance in star-forming (H II) regions agrees with the present value for the local interstellar medium, but seems to be incompatible with the stellar production rates inferred from observations of planetary nebulae, which provide a direct test of stellar evolution theory. Here we develop our earlier observations, which, when combined with recent theoretical developments in our understanding of light-element synthesis and destruction in stars, allow us to determine an upper limit for the primordial abundance of 3He relative to hydrogen: 3He/H = (1.1 +/- 0.2) x 10(-5). The primordial density of all baryons determined from the 3He data is in excellent agreement with the densities calculated from other cosmological probes. The previous conflict is resolved because most solar-mass stars do not produce enough 3He to enrich the interstellar medium significantly.