Corrêa-Velloso Juliana C, Bartlett Paula J, Brumer Robert, Gaspers Lawrence D, Ulrich Henning, Thomas Andrew P
Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
iScience. 2021 Sep 16;24(10):103139. doi: 10.1016/j.isci.2021.103139. eCollection 2021 Oct 22.
Extracellular agonists linked to inositol-1,4,5-trisphosphate (IP) formation elicit cytosolic Ca oscillations in many cell types, but despite a common signaling pathway, distinct agonist-specific Ca spike patterns are observed. Using qPCR, we show that rat hepatocytes express multiple purinergic P2Y and P2X receptors (R). ADP acting through P2Y1R elicits narrow Ca oscillations, whereas UTP acting through P2Y2R elicits broad Ca oscillations, with composite patterns observed for ATP. P2XRs do not play a role at physiological agonist levels. The discrete Ca signatures reflect differential effects of protein kinase C (PKC), which selectively modifies the falling phase of the Ca spikes. Negative feedback by PKC limits the duration of P2Y1R-induced Ca spikes in a manner that requires extracellular Ca. By contrast, P2Y2R is resistant to PKC negative feedback. Thus, the PKC leg of the bifurcated IP signaling pathway shapes unique Ca oscillation patterns that allows for distinct cellular responses to different agonists.
与肌醇-1,4,5-三磷酸（IP）形成相关的细胞外激动剂可在多种细胞类型中引发胞质钙振荡，然而，尽管信号通路相同，但却观察到不同激动剂特异性的钙峰模式。通过定量聚合酶链反应（qPCR），我们发现大鼠肝细胞表达多种嘌呤能P2Y和P2X受体（R）。通过P2Y1R起作用的ADP引发狭窄的钙振荡，而通过P2Y2R起作用的UTP引发宽泛的钙振荡，ATP则呈现复合模式。在生理激动剂水平下，P2XRs不起作用。离散的钙信号反映了蛋白激酶C（PKC）的不同作用，PKC选择性地改变钙峰的下降阶段。PKC的负反馈以需要细胞外钙的方式限制了P2Y1R诱导的钙峰持续时间。相比之下，P2Y2R对PKC负反馈具有抗性。因此，分叉的IP信号通路中的PKC分支塑造了独特的钙振荡模式，使得细胞对不同激动剂产生不同的反应。
