Publications

RATIONALE

Calmodulin (CaM) mutations are associated with an autosomal dominant syndrome of ventricular arrhythmia and sudden death that can present with divergent clinical features of catecholaminergic polymorphic ventricular tachycardia (CPVT) or long QT syndrome (LQTS). CaM binds to and inhibits ryanodine receptor (RyR2) Ca release channels in the heart, but whether arrhythmogenic CaM mutants alter RyR2 function is not known.

OBJECTIVE

To gain mechanistic insight into how human CaM mutations affect RyR2 Ca channels.

METHODS AND RESULTS

We studied recombinant CaM mutants associated with CPVT (N54I and N98S) or LQTS (D96V, D130G, and F142L). As a group, all LQTS-associated CaM mutants (LQTS-CaMs) exhibited reduced Ca affinity, whereas CPVT-associated CaM mutants (CPVT-CaMs) had either normal or modestly lower Ca affinity. In permeabilized ventricular myocytes, CPVT-CaMs at a physiological intracellular concentration (100 nmol/L) promoted significantly higher spontaneous Ca wave and spark activity, a typical cellular phenotype of CPVT. Compared with wild-type CaM, CPVT-CaMs caused greater RyR2 single-channel open probability and showed enhanced binding affinity to RyR2. Even a 1:8 mixture of CPVT-CaM:wild-type-CaM activated Ca waves, demonstrating functional dominance. In contrast, LQTS-CaMs did not promote Ca waves and exhibited either normal regulation of RyR2 single channels (D96V) or lower RyR2-binding affinity (D130G and F142L). None of the CaM mutants altered Ca/CaM binding to CaM-kinase II.

CONCLUSIONS

A small proportion of CPVT-CaM is sufficient to evoke arrhythmogenic Ca disturbances, whereas LQTS-CaMs do not. Our findings explain the clinical presentation and autosomal dominant inheritance of CPVT-CaM mutations and suggest that RyR2 interactions are unlikely to explain arrhythmogenicity of LQTS-CaM mutations.

Selenium is an essential trace element important to neurotransmission, but toxic at high levels. Some studies suggest beneficial effects on mood. We assessed the association of selenium exposure with presence of depressive symptoms. Selenium exposure was measured in toenail samples collected in 1987 from 3735 US participants (age 20-32 years) and depressive symptoms assessed in 1990, 1995, 2000, 2005, and 2010 using the Center for Epidemiologic Studies Depression Scale (CES-D). Binary and polytomous logistic regression models were used to assess the relation of log2(selenium) and selenium quintiles with presence of depressive symptoms (CES-D score≥27 or on antidepressant medication). Relative to selenium quintile 1, the adjusted odds ratio (OR) for having depressive symptoms in 1990 for quintile 5 was 1.59 (95% CI: 1.01, 2.51) and a unit increase in log2(selenium), which represents a doubling of the selenium level, was associated with an OR=2.03 (95% CI: 1.12, 3.70). When examining 1, 2 or 3+ exams vs. no exams with symptoms, the OR for quintile 5 was 1.73 (1.04, 2.89) for 3+ exams and for one exam and two exams, there were no associations. In a generalized estimating equations longitudinal model, a doubling of the selenium level was associated with a 56% higher odds of having depressive symptoms at an exam. Contrary to previously reported findings related to mood, higher level of selenium exposure was associated with presence of elevated depressive symptoms. More research is needed to elucidate the role of selenium in depressive disorders.