β1-Adrenergic Receptor Signaling Activates the Epithelial Calcium Channel, Transient Receptor Potential Vanilloid Type 5 (TRPV5), via the Protein Kinase A Pathway

One of the crucial cardiac signaling pathways is cAMP-mediated PKA signal transduction, which is regulated by a family of scaffolding proteins, i.e., A-kinase anchoring proteins (AKAPs). Muscle-specific AKAP (mAKAP) partly regulates cardiac cAMP/PKA signaling by binding to PKA and phosphodiesterase 4D3 (PDE4D3), among other proteins, and plays a central role in modulating cardiac remodeling. Moreover, genetics plays an incomparable role in modifying the risk of cardiovascular diseases (CVDs). Single-nucleotide polymorphisms (SNPs) in various proteins have especially been shown to predispose individuals to CVDs. Hence, we hypothesized that human mAKAP polymorphisms found in humans with CVDs alter the cAMP/PKA pathway, influencing the susceptibility of individuals to CVDs. Our computational analyses revealed two mAKAP SNPs found in cardiac disease-related patients with the highest predicted deleterious effects, Ser 1653 Arg (S1653R) and Glu 2124 Gly (E2124G). Coimmunoprecipitation data in human embryonic kidney-293T cells showed that the S1653R SNP, present in the PDE4D3-binding domain of mAKAP, changed the binding of PDE4D3 to mAKAP and that the E2124G SNP, flanking the 3'-PKA binding domain, changed the binding of PKA before and after stimulation with isoproterenol. These SNPs significantly altered intracellular cAMP levels, global PKA activity, and cytosolic PDE activity compared with the wild type before and after isoproterenol stimulation. PKA-mediated phosphorylation of pathological markers was found to be upregulated after cell stimulation in both mutants. In conclusion, human mAKAP polymorphisms may influence the propensity of developing CVDs by affecting cAMP/PKA signaling, supporting the clinical significance of PKA-mAKAP-PDE4D3 interactions. NEW & NOTEWORTHY We found that single-nucleotide polymorphisms in muscle-specific A-kinase anchoring protein found in human patients with cardiovascular diseases significantly affect the cAMP/PKA signaling pathway. Our results showed, for the first time, that human muscle-specific A-kinase anchoring protein polymorphisms might alter the susceptibility of individuals to develop cardiovascular diseases with known underlying molecular mechanisms.

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“…1C). The mRNA expression of ␤ 1 -and ␤ 2 -adrenergic receptors has been shown successfully in HEK cells elsewhere (44).…”

Section: S1653r and E2124g Makap Missense Snps Were Found Inmentioning

confidence: 99%

Human muscle-specific A-kinase anchoring protein polymorphisms modulate the susceptibility to cardiovascular diseases by altering cAMP/PKA signaling

Suryavanshi

Jadhav

Anderson

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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“…Regarding agonists, the β-adrenergic receptor (β-AR) comprises β1-AR, β2-AR, and β3-AR, with β1-AR and β2-AR primarily distributed in the renal DCT2/CNT [ 153 ]. The β1-AR agonist, dobutamine, upregulates the expression of cAMP in HEK293 cells, stimulates TRPV5 in Ca 2+ uptake, and enhances the activity of the TRPV5 channel by phosphorylating T709 residues via the PKA pathway [ 154 ]. Streptozotocin-induced diabetes significantly increases TRPV5 mRNA expression in rats, and renal immunofluorescence sections demonstrate a significant increase in TRPV5 expression [ 155 ].…”

Section: Overview Of Trpv5mentioning

confidence: 99%

Alterations in the microenvironment and the effects produced of TRPV5 in osteoporosis

Luo

Zhang

et al. 2023

J Transl Med

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The pathogenesis of osteoporosis involves multiple factors, among which alterations in the bone microenvironment play a crucial role in disrupting normal bone metabolic balance. Transient receptor potential vanilloid 5 (TRPV5), a member of the TRPV family, is an essential determinant of the bone microenvironment, acting at multiple levels to influence its properties. TRPV5 exerts a pivotal influence on bone through the regulation of calcium reabsorption and transportation while also responding to steroid hormones and agonists. Although the metabolic consequences of osteoporosis, such as loss of bone calcium, reduced mineralization capacity, and active osteoclasts, have received significant attention, this review focuses on the changes in the osteoporotic microenvironment and the specific effects of TRPV5 at various levels.

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“…Upon binding to its receptor (PTH1R) in the DCT, PTH stimulates active Ca 2+ reabsorption via the adenylyl cyclase–cAMP–protein kinase A (PKA) pathway to directly phosphorylate TRPV5 (but not TRPV6), thereby increasing single channel open probability [111]. The same signaling pathway has been recently reported to play a role in regulation of TRPV5 activity by β1-adrenergic receptor signaling [112], however, anti-calciuretic effects of adrenergic signaling in the kidney are not well described in clinic. In addition, PTH has been reported to affect TRPV5 function via other molecular mechanisms likely involving phosphorylation of the channel by PKC [113-115].…”

Section: Introductionmentioning

confidence: 99%

Role of renal TRP channels in physiology and pathology

et al. 2015

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Kidneys critically contribute to the maintenance of whole-body homeostasis by governing water and electrolyte balance, regulating extracellular fluid volume, plasma osmolality and blood pressure. Renal function is regulated by numerous systemic endocrine and local mechanical stimuli. Kidneys possess a complex network of membrane receptors, transporters and ion channels which allows responding to this wide array of signaling inputs in an integrative manner. Transient receptor potential (TRP) channel family members with diverse modes of activation, varied permeation properties and capability to integrate multiple downstream signals are pivotal molecular determinants of renal function all along the nephron. This review summarizes experimental data on the role of TRP channels in a healthy mammalian kidney and discusses their involvement in renal pathologies.

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β1-Adrenergic Receptor Signaling Activates the Epithelial Calcium Channel, Transient Receptor Potential Vanilloid Type 5 (TRPV5), via the Protein Kinase A Pathway

Cited by 10 publications

References 39 publications

Human muscle-specific A-kinase anchoring protein polymorphisms modulate the susceptibility to cardiovascular diseases by altering cAMP/PKA signaling

Human muscle-specific A-kinase anchoring protein polymorphisms modulate the susceptibility to cardiovascular diseases by altering cAMP/PKA signaling

Alterations in the microenvironment and the effects produced of TRPV5 in osteoporosis

Role of renal TRP channels in physiology and pathology

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