Circulation research
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Circulation research · Mar 2006
Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice.
Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II (BMPR-II) receptor underlie the majority (>70%) of cases of familial pulmonary arterial hypertension (FPAH), and dysfunction of BMP signaling has been implicated in other forms of PAH. The reduced disease gene penetrance in FPAH indicates that other genetic and/or environmental factors may also be required for the clinical manifestation of disease. Of these, the serotonin pathway has been implicated as a major factor in PAH pathogenesis. ⋯ Furthermore, pulmonary artery smooth muscle cells from BMPR2(+/-) mice exhibited a heightened DNA synthesis and activation of extracellular signal-regulated kinase 1/2 in response to serotonin compared with wild-type cells. In vitro and in vivo experiments suggested that serotonin inhibits BMP signaling via Smad proteins and the expression of BMP responsive genes. These findings provide the first evidence for an interaction between BMPR-II-mediated signaling and the serotonin pathway, perturbation of which may be critical to the pathogenesis of PAH.
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Circulation research · Mar 2006
No apparent requirement for neuronal sodium channels in excitation-contraction coupling in rat ventricular myocytes.
The majority of Na channels in the heart are composed of the tetrodotoxin (TTX)-resistant (KD, 2 to 6 micromol/L) "cardiac" NaV1.5 isoform; however, TTX-sensitive (KD, 1 to 25 nmol/L) "neuronal" Na channel isoforms have recently been detected in several cardiac preparations. In the present study, we determined the functional subcellular localization of Na channel isoforms (according to their TTX sensitivity) in rat ventricular myocytes by recording INa in control and detubulated myocytes. We found that TTX-sensitive INa (KD, &8.8 nmol/L) makes up 14+/-3% of total INa in control and < or =4% in detubulated myocytes and calculated that &80% of TTX-sensitive INa is located in the t-tubules, where it generates &1/3 of t-tubular INa. ⋯ TTX decreased the rate of depolarization of the action potential by 10% but did not delay the rise of systolic Ca2+ in the center of the cell (transverse confocal line scan), suggesting that TTX-sensitive INa does not play a role in synchronizing Ca2+ release at the t-tubules; the amplitude of the Ca2+ transient and contraction were also unchanged by 200 nmol/L TTX. The quantity of charge entering via ICa elicited by control or TTX action potential waveforms was similar, suggesting that the trigger for Ca2+ release is not altered by blocking TTX-sensitive INa. We conclude that neuronal INa is concentrated at the t-tubules, but there is no evidence of a requirement for these channels in normal excitation-contraction coupling in ventricular myocytes.