Mechanisms underlying angiotensin II-induced calcium oscillations.
To gain insight into the mechanisms that underlie angiotensin II (ANG II)-induced cytoplasmic Ca2+ concentration ([Ca]cyt) oscillations in medullary pericytes, we expanded a prior model of ion fluxes. ANG II stimulation was simulated by doubling maximal inositol trisphosphate (IP3) production and imposing a 90% blockade of K+ channels. We investigated two configurations, one in which ryanodine receptors (RyR) and IP3 receptors (IP3R) occupy a common store and a second in which they reside on separate stores. Our results suggest that Ca2+ release from stores and import from the extracellular space are key determinants of oscillations because both raise [Ca] in subplasmalemmal spaces near RyR. When the Ca2+-induced Ca2+ release (CICR) threshold of RyR is exceeded, the ensuing Ca2+ release is limited by Ca2+ reuptake into stores and export across the plasmalemma. If sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pumps do not remain saturated and sarcoplasmic reticulum Ca2+ stores are replenished, that phase is followed by a resumption of leak from internal stores that leads either to [Ca]cyt elevation below the CICR threshold (no oscillations) or to elevation above it (oscillations). Our model predicts that oscillations are more prone to occur when IP3R and RyR stores are separate because, in that case, Ca2+ released by RyR during CICR can enhance filling of adjacent IP3 stores to favor a high subsequent leak that generates further CICR events. Moreover, the existence or absence of oscillations depends on the set points of several parameters, so that biological variation might well explain the presence or absence of oscillations in individual pericytes.
Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155, USA. aurelie.edwards@tufts.edu
Aurélie
A
Edwards
Thomas L
TL
Pallone
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007679:Kidney Medulla / Q000098:blood supply*; D008954:Models, Biological; D020286:Pericytes / Q000166:cytology / Q000378:metabolism*; D011189:Potassium Chloride / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
D053496:Inositol 1,4,5-Trisphosphate Receptors; D019837:Ryanodine Receptor Calcium Release Channel; D000804:Angiotensin II; D011189:Potassium Chloride; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium