Direct Interaction of CaVβ with Actin Up-regulates L-type Calcium Currents in HL-1 Cardiomyocytes

Stölting, Gabriel; Oliveira, Regina Campos de; Guzman, Raul E.; Miranda-Laferte, Erick; Conrad, Rachel A.; Jordan, Nadine; Schmidt, Silke; Hendriks, Johnny; Gensch, Thomas; Hidalgo, Patricia

doi:10.1074/jbc.m114.573956

Cited by 36 publications

(56 citation statements)

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“…Properties of I f current in HL-1 cells are similar to those in SANC; inhibition of I f current in HL-1 cells as in SANC significantly suppresses diastolic depolarization and reduces automaticity. L-type and T-type Ca channels, inward rectifier K + channels, and Stim1 are also expressed in HL-1 cells [25–28]. The effects of application of thapsigargin and ryanodine to HL-1 cells as well as effects of PKA activation are the same as in SANC.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…Could the disruption of F-actin be responsible for the spatial disorganization of the Ca V 1.3 Ca 2+ channels? It has been suggested that a direct association between Ca V β 2 and F-actin promotes the directional transport of Ca 2+ channels to the plasma membrane of cardiomyocytes (34), and, at the ribbon synapse of salamander photoreceptors, the confinement of Ca 2+ channels beneath the ribbon is regulated by actin and membrane cholesterol (35). The disruption of F-actin with latrunculin-A in WT IHCs has been shown to disrupt the spatial distribution of Ca V 1.3 Ca 2+ channels (23) in a manner similar to that observed here, in the active zones of IHCs lacking clarin-1 from the 2 types of mutant mice.…”

Section: Hearing Rescue By Virus-mediated Gene Transfer Into the Ihcsmentioning

confidence: 99%

Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

Dulon¹,

Papal²,

Patni³

et al. 2018

Journal of Clinical Investigation

104

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“…In fact, in the presence of cytochalasin D, which disrupts actin polymerization, over-expression of Ca v β 2 failed to stimulate L-type currents, as is observed in cells with intact actin cytoskeleton. Together, these findings highlight the importance of Ca v β for the surface expression of VGCC and point to a possible mechanism in which Ca v β promote the transport of the channel to the plasma membrane via its interaction with actin (Table 3) [102]. For several decades, the described functions of Ca v β have been exclusively linked to VGCC.…”

Section: Actin the Most Recently Identified Partner Of Ca V βmentioning

confidence: 95%

“…In their recent study, Stölting et al [102] uncovered a direct interaction between Ca v β 2 and actin filaments. The interaction was demonstrated in vitro as well as in vivo, it involves both, the SH3 and GK domains, suggesting that binding to actin is a property shared by all Ca v βs.…”

Section: Actin the Most Recently Identified Partner Of Ca V βmentioning

confidence: 97%

“…The interaction involves both SH3 and GK domains conserved among all Ca v βs [102] a truncated proline, serine and threonine domain and a unique serine-rich tail (S tail). In fact, co-expression of Pax6(S) with a Ca 2 + channel complex including Ca v β 3 in Xenopus oocytes did not affect channel properties but made Ca v β 3 capable of translocating from the cytoplasm to the nucleus to repress the transcriptional activity of Pax6(S).…”

Section: Actin the Most Recently Identified Partner Of Ca V βmentioning

confidence: 99%

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Protein partners of the calcium channel β subunit highlight new cellular functions

Rima

Daghsni

Fajloun

et al. 2016

Biochemical Journal

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Calcium plays a key role in cell signalling by its intervention in a wide range of physiological processes. Its entry into cells occurs mainly via voltage-gated calcium channels (VGCC), which are found not only in the plasma membrane of excitable cells but also in cells insensitive to electrical signals. VGCC are composed of different subunits, α1, β, α2δ and γ, among which the cytosolic β subunit (Cavβ) controls the trafficking of the channel to the plasma membrane, its regulation and its gating properties. For many years, these were the main functions associated with Cavβ. However, a growing number of proteins have been found to interact with Cavβ, emphasizing the multifunctional role of this versatile protein. Interestingly, some of the newly assigned functions of Cavβ are independent of its role in the regulation of VGCC, and thus further increase its functional roles. Based on the identity of Cavβ protein partners, this review emphasizes the diverse cellular functions of Cavβ and summarizes both past findings as well as recent progress in the understanding of VGCC.

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Direct Interaction of CaVβ with Actin Up-regulates L-type Calcium Currents in HL-1 Cardiomyocytes

Cited by 36 publications

References 50 publications

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

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

Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

Protein partners of the calcium channel β subunit highlight new cellular functions

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