A CaMKII/PDE4D negative feedback regulates cAMP signaling

Mika, Delphine; Richter, Wito; Conti, Marco

doi:10.1073/pnas.1419992112

Cited by 60 publications

(40 citation statements)

References 45 publications

(42 reference statements)

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“…Using this approach, the authors identified phosphodiesterase 4D (PDE4D) as a substrate of SIK1 and provided multiple pieces of evidence that phosphorylation by SIK1 activates PDE4D, thus promoting the degradation of cAMP and reducing insulin secretion. These findings were corroborated by a recent study in another excitable cell type, cardiomyocytes, where PDE4D was part of a negative feedback loop buffering cAMP levels (10).…”

supporting

confidence: 76%

A Dash of Salt-Inducible Kinase 1 Keeps Insulin Levels in Check

Aikin

Rosenberg

2015

Diabetes

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The precise control of insulin release from pancreatic b-cells in response to changes in circulating glucose levels is essential for maintaining metabolic homeostasis. Understanding the pathways coupling insulin secretion to blood glucose levels is critical for the development of new strategies to treat a variety of metabolic disorders, including type 2 diabetes. In this issue of Diabetes, Kim et al.(1) propose a novel regulatory feedback mechanism operating within b-cells that acts to reduce insulin secretion.Within b-cells, cyclic AMP (cAMP) acts as a positive regulator of insulin secretion by both nontranscriptional and transcriptional mechanisms. Increased cAMP levels can directly potentiate insulin granule release, as well as regulate genes involved in b-cell function and survival (2-4). Thus, cAMP levels within b-cells must be tightly regulated in order to ensure proper secretion of adequate amounts of insulin. The importance of cAMP in type 2 diabetes is underscored by the proliferation of incretinbased drugs on the market over the past decade, including glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase-4 inhibitors, which potentiate insulin release by increasing cAMP signaling in b-cells (5). Thus, developing our understanding of the mechanisms controlling cAMP levels in b-cells has great potential to uncover new therapeutic targets for the treatment of type 2 diabetes.The salt-inducible kinases (SIKs), members of the AMPactivated protein kinase family, are negative regulators of cAMP signaling and regulate metabolic processes in various tissues such as the liver and adipose tissue. SIK1 and SIK2 often act as inducible repressors of cAMP signals as they are transcriptional targets of cAMP signaling but can then negatively regulate cAMP-mediated signaling. This negative feedback loop plays a key role in controlling different biological processes, including circadian rhythm (6), the coupling of fasting/feeding states to gluconeogenesis in the liver (7,8), and lipolysis in adipocytes (9).Kim et al.(1) sought to examine the role of SIK1 in glucose homeostasis in mice. The authors observed that SIK1 +/2 mice had reduced blood glucose levels and increased plasma insulin levels compared with wild-type control mice, suggesting that reduced SIK1 levels led to increased insulin release. In order to more directly assess the role of SIK1 in insulin secretion, the authors compared glucose-stimulated insulin secretion (GSIS) from islets isolated from control and SIK1 +/2 mice. Using both static-and perfusion-based GSIS assays, the authors found that SIK1 +/2 islets secreted elevated levels of insulin following glucose stimulation. As SIK1 +/2 islets also displayed elevated cAMP, the authors set out to examine the role of SIK1 in mediating cAMP levels (Fig. 1A).In order to shed light on how SIK1 may be controlling cAMP levels, the authors sought to identify novel substrates of SIK1. Using an in vitro kinase assay, the authors defined a SIK1 phosphorylation consensus sequence and used this to identify p...

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supporting

confidence: 76%

A Dash of Salt-Inducible Kinase 1 Keeps Insulin Levels in Check

Aikin

Rosenberg

2015

Diabetes

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“…PDE4 is also expressed in SANC and has been implicated in their action potential firing rate [56]. A recent report on mouse neonatal cardiac myocytes provides evidence that PDE4D is also activated by Ca 2+ via CaMKII [57]. Co-immunoprecipitation of PDEs and Ca 2+ cycling proteins in ventricular cells indicate that PDE3-4 are linked to SR SERCA-2 and RyR, two of the most important Ca 2+ cycling proteins in regulation of SANC automaticity [58–60].…”

Section: Discussionmentioning

confidence: 99%

Ca2+/calmodulin-activated phosphodiesterase 1A is highly expressed in rabbit cardiac sinoatrial nodal cells and regulates pacemaker function

Lukyanenko

Younès

Lyashkov

et al. 2016

Journal of Molecular and Cellular Cardiology

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Constitutive Ca2+/calmodulin (CaM)-activation of adenylyl cyclases (ACs) types 1 and 8 in sinoatrial nodal cells (SANC) generates cAMP within lipid-raft-rich microdomains to initiate cAMP–protein kinase A (PKA) signaling, that regulates basal state rhythmic action potential firing of these cells. Mounting evidence in other cell types points to a balance between Ca2+-activated counteracting enzymes, ACs and phosphodiesterases (PDEs) within these cells. We hypothesized that the expression and activity of Ca2+/CaM-activated PDE Type 1A is higher in SANC than in other cardiac cell types. We found that PDE1A protein expression was 5-fold higher in sinoatrial nodal tissue than in left ventricle, and its mRNA expression was 12-fold greater in the corresponding isolated cells. PDE1 activity (nimodipine-sensitive) accounted for 39% of the total PDE activity in SANC lysates, compared to only 4% in left ventricular cardiomyocytes (LVC). Additionally, total PDE activity in SANC lysates was lowest (10%) in lipid-raft-rich and highest (76%) in lipid-raft-poor fractions (equilibrium sedimentation on a sucrose density gradient). In intact cells PDE1A immunolabeling was not localized to the cell surface membrane (structured illumination microscopy imaging), but located approximately within about 150 nm inside of immunolabeling of hyperpolarization-activated cyclic nucleotide-gated potassium channels (HCN4), which reside within lipid-raft-rich microenvironments. In permeabilized SANC, in which surface membrane ion channels are not functional, nimodipine increased spontaneous SR Ca2+ cycling. PDE1A mRNA silencing in HL-1 cells increased the spontaneous beating rate, reduced the cAMP, and increased cGMP levels in response to IBMX, a broad spectrum PDE inhibitor (detected via fluorescence resonance energy transfer microscopy). We conclude that signaling via cAMP generated by Ca2+/CaM-activated AC in SANC lipid raft domains is limited by cAMP degradation by Ca2+/CaM-activated PDE1A in non-lipid raft domains. This suggests that local gradients of [Ca2+]–CaM or different AC and PDE1A affinity regulate both cAMP production and its degradation, and this balance determines the intensity of Ca2+-AC-cAMP-PKA signaling that drives SANC pacemaker function.

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“…Resetting may involve re-activation of CaMKII: elevation of intracellular calcium with strong stimulation of bPAC activates CaMKII ( Figure S10B ), while inhibiting CaMKII with KN93 results in a high frequency of successive eruptions ( Figure S10C ). In mammalian cardiomyocytes, CaMKII is known to phosphorylate and activate phosphodiesterase 4D 43 , which degrades cAMP. There are signs that this mechanism may be at work in the Crz neurons as well: RNAi knockdown of the PDE4 homolog dunce shortens the duration of the voltage requirement ( Figure 2F ), activation of CaMKII dramatically reduces baseline cAMP levels ( Figure 6D ), and a potential CaMKII phosphorylation site on PDE4 seems to be conserved on dunce (our observation).…”

Section: Discussionmentioning

confidence: 99%

Biochemical computation underlying behavioral decision-making

Thornquist

et al. 2020

Preprint

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7Computations in the brain are broadly assumed to emerge from patterns of fast electrical 8 activity. Challenging this view, we show that a male fly's decision to persist in mating, 9 even through a potentially lethal threat, hinges on biochemical computations that enable 10 processing over minutes to hours. Each neuron in a recurrent network measuring time 11 into mating contains slightly different internal molecular estimates of elapsed time. 12Protein Kinase A (PKA) activity contrasts this internal measurement with input from the 13 other neurons to represent evidence that the network's goal has been achieved. When 14 consensus is reached, PKA pushes the network toward a large-scale and synchronized 15 burst of calcium influx, which we call an eruption. The eruption functions like an action 16 potential at the level of the network, transforming deliberation within the network into an 17 all-or-nothing output, after which the male will no longer sacrifice his life to continue 18 mating. We detail the continuous transformation between interwoven molecular and 19 electrical information over long timescales in this system, showing how biochemical 20 activity, invisible to most large scale recording techniques, is the key computational 21 currency directing a life-or-death decision. 22 23 24 25 32 33A fundamental problem in neural computation stems from the need for neurons within a 34 network to communicate without triggering premature responses in downstream 35 circuitry 1-3 . This problem is compounded when the computations are performed over 36 long timescales, as in many decision-making paradigms 4 . In single neurons, the action 37 potential solves an analogous problem by transforming accumulated positive and 38 negative inputs into a transient, all-or-nothing output that is broadcasted to postsynaptic 39 targets. Here we identify a similar mechanism acting at the network level and over 40 timescales ranging from seconds to hours, which we call an eruption. 42The Corazonin-expressing (Crz) neurons of the male abdominal ganglion comprise an 43 exceptionally tractable system for investigating neuronal networks and behavioral 44 control. These four neurons drive two simultaneous and crucial events in the lives of the 45 male and his mating partner: i) the transfer of sperm from the male to the female 5 and ii) 46 a transition out of a period of insurmountably high motivation to continue mating 6 . Both of 47 these events occur six minutes after a mating begins and are under the control of a 48 molecular timer encoded by the slowly-decaying autophosphorylation of the kinase 49 CaMKII 6 . We show that the Crz neurons use cyclic AMP (cAMP) signaling to average 50 evidence about the passage of time across the network and generate an eruption that 51 signals to downstream circuitry only when a consensus is reached. In addition to 52 revealing a new network phenomenon, these results explain the function of CaMKII in 53 the only mechanism for interval timing yet to be described. 55 RESULTS 57The Crz neurons form a recu...

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A CaMKII/PDE4D negative feedback regulates cAMP signaling

Cited by 60 publications

References 45 publications

A Dash of Salt-Inducible Kinase 1 Keeps Insulin Levels in Check

A Dash of Salt-Inducible Kinase 1 Keeps Insulin Levels in Check

Ca2+/calmodulin-activated phosphodiesterase 1A is highly expressed in rabbit cardiac sinoatrial nodal cells and regulates pacemaker function

Biochemical computation underlying behavioral decision-making

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