Calcium Sparks Unleashed in Vascular Smooth Muscle
Lessons From the RyR3 Knockout Mouse
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Hypertension is a progressive disease involving an increase in arterial constriction. It constitutes a major risk factor leading to stroke, heart disease, and kidney failure. Understanding the molecular pathways involved in arterial tone regulation is crucial to increasing our understanding of blood pressure regulation. Recently, a novel mechanism involving small-localized bursts of calcium inside vascular smooth muscle cells, termed Ca2+ sparks, was identified that acts as a negative feedback mechanism that opposes vasoconstriction.1
Ca2+ Sparks in Muscle
Ca2+ sparks are thought to be the elementary functional Ca2+ release signals in heart, skeletal, and smooth muscle cells.1–4 Ca2+ sparks are but one example of the increasing complexity in Ca2+ signaling in the spatial and temporal domain in a variety of tissues including arterial smooth muscle.5 Ca2+ sparks result from the opening of several or the coordinated opening of many, tightly clustered ryanodine receptor Ca2+ release channels (RyRs) in the sarcoplasmic reticulum (SR) of muscle cells.6,7 In arterial smooth muscle and intact arteries, Ca2+ sparks are observed just under the cell membrane consistent with a predominant subsarcolemmal localization of the RyR Ca2+ release channels in the sarcoplasmic reticulum.3,8
Function, Distribution, and Localization of RyR Isoforms
The mammalian RyRs are encoded by 3 different genes (RYR1, RYR2, and RYR3). Initial DNA cloning studies in mammalian tissues have assigned the names RyR1 to the subtype dominantly expressed in skeletal muscle, RyR2 to the one in cardiac muscle and RyR3 in brain tissue, respectively.9,10 The functional properties of RyR1 and RyR2 are well studied because of their dominant expression and role in excitation-contraction coupling in skeletal and cardiac muscle, respectively. RyR1 is essential for EC coupling in skeletal muscle and is thought to act as the Ca2+ release channel that is mechanically linked to the sarcolemmal voltage-sensor constituted …