Sorbonne Université, Université Pierre et Marie Curie (UPMC), Institut de Biologie Paris-Seine (IBPS), UMR CNRS 8256 Adaptation biologique et vieillissement (B2A), 75005 Paris, France.
UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne (URCA), UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Laboratoire Signalisation et Récepteurs Matriciels (SiRMa), Campus Moulin de la Housse, 51687 Reims, France.
Biochim Biophys Acta Mol Cell Res. 2018 Sep;1865(9):1326-1340. doi: 10.1016/j.bbamcr.2018.06.012. Epub 2018 Jun 22.
Here, we cloned a new family of four adenylyl cyclase (AC) splice variants from interleukin-1β (IL-1β)-transdifferentiated vascular smooth muscle cells (VSMCs) encoding short forms of AC8 that we have named "AC8E-H". Using biosensor imaging and biochemical approaches, we showed that AC8E-H isoforms have no cyclase activity and act as dominant-negative regulators by forming heterodimers with other full-length ACs, impeding the traffic of functional units towards the plasma membrane. The existence of these dominant-negative isoforms may account for an unsuspected additional degree of cAMP signaling regulation. It also reconciles the induction of an AC in transdifferentiated VSMCs with the vasoprotective influence of cAMP. The generation of alternative splice variants of ACs may constitute a generalized strategy of adaptation to the cell's environment whose scope had so far been ignored in physiological and/or pathological contexts.
在这里，我们从白细胞介素-1β（IL-1β）转化的血管平滑肌细胞（VSMCs）中克隆了一个新的腺苷酸环化酶（AC）剪接变体家族，该家族编码 AC8 的短形式，我们将其命名为“AC8E-H”。使用生物传感器成像和生化方法，我们表明 AC8E-H 异构体没有环化酶活性，并且通过与其他全长 AC 形成异二聚体作为显性负调节剂起作用，阻碍功能性单位向质膜的运输。这些显性负性异构体的存在可能解释了 cAMP 信号转导调节的一个意想不到的额外程度。它还调和了转分化的 VSMCs 中 AC 的诱导与 cAMP 的血管保护作用。AC 的可变剪接变体的产生可能构成一种适应细胞环境的普遍策略，其范围迄今为止在生理和/或病理环境中被忽视。
