• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • br Sources of funding br Disclosures br Acknowledgments br


    Sources of funding
    Introduction Insulin secretion from pancreatic β cells is a fundamental process to maintain blood glucose homeostasis. During glucose-stimulated insulin secretion, high glucose causes closure of ATP-sensitive K+ channels (KATP channels), subsequently evokes β cell depolarization, leading to activation of voltage dependent Ca2+ channels, and then stimulating insulin secretion [1]. In this process, voltage-dependent K+ channels (KV), which is in charge of membrane repolarization, provide a negative modulation for insulin secretion. Increasing body of studies have shown that blockade of the KV channel enhances insulin secretion from β cells [2], [3], [4], indicating that the Kv channel is a potential target for the treatment of type 2 diabetes (T2D). P2Y receptors (P2YR) are a family of purinergic G protein-coupled receptors, which could be stimulated by extracellular nucleotides [5]. In pancreatic β cells, activation of P2YR has long been shown to stimulate insulin secretion in a glucose-dependent manner [6], [7]. Intravenous or oral administration of ADPβS, a potent P2YR agonist, were reported to improve glucose tolerance [6], [8]. These observations indicate that P2YR agonists might be good candidates for future therapeutic drug developments for T2D. We and others have demonstrated that the AC/cAMP signaling pathway mediates the P2YR-modulated insulinotropic action [9], [10]. Moreover, our previous study has show that P2YR-modulated insulin secretion is predominantly mediated by cAMP downstream effector, Epac (exchange protein directly activated by cAMP). We found that activation of P2YR inhibits Kv channels through Epac pathway, and Kv inhibition in turn prolongs pramipexole dihydrochloride duration and potentiates insulin secretion [10]. Of note, inhibition of Kv channels has been reported to potentiate insulin secretion in a glucose-dependent manner [3], [4], [11], this secretory pattern apparently fits the characterization of P2YR-modulated insulin secretion, indicating that the Kv channel is the important contributor in P2YR-modulated insulin secretion. However, the interplay between Epac and the Kv channel remains to be elucidated.
    Materials and methods
    Results and discussion
    Conflict of interest
    Introduction Cyclic adenosine monophosphate (cAMP) regulates various cellular functions in virtually all cell types, making it one of the most important second messenger molecules in cellular signaling [1]. CAMP signaling is embedded into a highly sophisticated system of proteins governing its synthesis, degradation and cellular actions in a cell type and context specific manner. In this system degradation of cAMP is catalyzed by 3′,5′-cyclic nucleotide phosphodiesterases (PDEs) [2]. PDE-dependent regulation of cAMP-signaling is organized by compartment specific expression of PDEs, which results in the generation of intracellular cAMP gradients [3]. PDEs thereby exist in a large diversity of 11 distinct family members with numerous isoforms and splice variants being yet identified [4], [5]. Of particular interest to the cardiovascular system are members of the PDE4 family. Vascular smooth muscle cells (SMCs) express PDE4A, PDE4B, as well as numerous variants of PDE4D [3]. While quiescent SMCs rely primarily on PDE3 for hydrolysis of cAMP, PDE4 activity surpasses PDE3 activity in SMCs that have been activated by growth factors or inflammatory cytokines [6], [7]. SMCs that become activated at sites of vascular injury undergo a phenotypic switch, in which silencing of contractile genes is paralleled by an increased cellular propensity to migrate, proliferate and secrete extracellular matrix proteins [8]. These activated or synthetic SMCs constitute an essential component of pathologic vascular remodeling and atherosclerosis formation [8], [9]. Abundant evidence has previously shown that increased cellular cAMP levels inhibit SMC activation [10], [11], [12]. Upregulation of PDE4 in response to inflammatory stimuli is consequently an obligate requirement for cAMP degradation and ensuing cell activation [13]. Considering the shift from PDE3 to PDE4 activity occurring during SMC phenotypic switch, PDE4 inhibition has been implicated as a promising target to selectively repress SMC driven remodeling following vascular injury.