Research ArticleCalcium signaling

TRPML1 channels initiate Ca2+ sparks in vascular smooth muscle cells

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Science Signaling  23 Jun 2020:
Vol. 13, Issue 637, eaba1015
DOI: 10.1126/scisignal.aba1015

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Lighting a spark from the lysosome

Ca2+ sparks in vascular smooth muscle cells are critical for blood vessel dilation and for blood pressure regulation. Thakore et al. showed that these Ca2+ sparks were initiated by Ca2+ released from lysosomes through the cation channel TRPML1 (see the Focus by Nieves-Cintron et al.). Lysosomes in contractile vascular smooth muscle cells were immobile and localized in close proximity to an ion channel that is part of the Ca2+ spark-generating pathway, whereas they were highly mobile in proliferative vascular smooth muscle cells (as is typical for most cell types). Vascular smooth muscle cells from mice deficient in TRPML1 did not generate Ca2+ sparks, and these mice were spontaneously hypertensive. Thus, TRPML1 generates the signal that initiates Ca2+ sparks to relax vascular smooth muscle and modulate blood pressure.


TRPML1 (transient receptor potential mucolipin 1) is a Ca2+-permeable, nonselective cation channel localized to the membranes of endosomes and lysosomes and is not present or functional on the plasma membrane. Ca2+ released from endosomes and lysosomes into the cytosol through TRPML1 channels is vital for trafficking, acidification, and other basic functions of these organelles. Here, we investigated the function of TRPML1 channels in fully differentiated contractile vascular smooth muscle cells (SMCs). In live-cell confocal imaging studies, we found that most endosomes and lysosomes in freshly isolated SMCs from cerebral arteries were essentially immobile. Using nanoscale super-resolution microscopy, we found that TRPML1 channels present in late endosomes and lysosomes formed stable complexes with type 2 ryanodine receptors (RyR2) on the sarcoplasmic reticulum (SR). Spontaneous Ca2+ signals resulting from the release of SR Ca2+ through RyR2s (“Ca2+ sparks”) and corresponding Ca2+-activated K+ channel activity are critically important for balancing vasoconstriction. We found that these signals were essentially absent in SMCs from TRPML1-knockout (Mcoln1−/−) mice. Using ex vivo pressure myography, we found that loss of this critical signaling cascade exaggerated the vasoconstrictor responses of cerebral and mesenteric resistance arteries. In vivo radiotelemetry studies showed that Mcoln1−/− mice were spontaneously hypertensive. We conclude that TRPML1 is crucial for the initiation of Ca2+ sparks in SMCs and the regulation of vascular contractility and blood pressure.

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