ANO4 (Anoctamin 4) Is a Novel Marker of Zona Glomerulosa That Regulates Stimulated Aldosterone Secretion

Maniero, Carmela; Scudieri, Paolo; Shaikh, Lalarukh Haris; Zhao, Wanfeng; Gurnell, Mark; Galietta, Luis J. V.

doi:10.1161/hypertensionaha.119.13287

Cited by 18 publications

(19 citation statements)

References 37 publications

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“…Based on our investigation, we suggest that these associations result mainly from reduced or loss of ANO4 activity in the affected tissues. The recently reported role of ANO4 in the regulation of aldosterone secretion fits into the observation that ANO4 is preferentially expressed in tissue with secretory activity [ 18 , 19 ].…”

Section: Discussionmentioning

confidence: 55%

“…Additionally, recently, literature reported a link between ANO4 expression and some disease mechanisms. The group of Brown and colleagues suggested that ANO4 might be involved in the regulation of aldosterone secretion [ 18 , 19 ]. Furthermore, active myelin-lesions in multiple sclerosis display increased levels of ANO4 expression [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

Reichhart

Milenkovic

Wetzel

et al. 2021

IJMS

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The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca2+-dependent ion channels and/or Ca2+-dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.

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Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

Reichhart

Milenkovic

Wetzel

et al. 2021

IJMS

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“…The Potassium Two Pore Domain Channel Subfamily K Member 5 ( KCNK5 or TASK2 ) channel is also consistently less expressed in APAs compared to normal adrenal cortex [ 65 ]. Recently, Anoctamin 4 ( ANO4 ), a calcium dependent chloride channel, was found to be significantly downregulated in APAs compared to normal ZG, independent of their respective mutation status [ 66 ]. Expression data on L-type and T-type voltage dependent calcium channels has demonstrated high CACNA1H expression in both normal adrenal glands and APAs, while CACNA1A, CACNA1C and CACNA1E expression was significantly upregulated in APAs [ 20 ].…”

Section: Resultsmentioning

confidence: 99%

Transcriptomics, Epigenetics, and Metabolomics of Primary Aldosteronism

Spyroglou

Piaditis

Kaltsas

et al. 2021

Cancers

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Introduction: Primary aldosteronism (PA) is the most common cause of endocrine hypertension, mainly caused by aldosterone-producing adenomas or hyperplasia; understanding its pathophysiological background is important in order to provide ameliorative treatment strategies. Over the past several years, significant progress has been documented in this field, in particular in the clarification of the genetic and molecular mechanisms responsible for the pathogenesis of aldosterone-producing adenomas (APAs). Methods: Systematic searches of the PubMed and Cochrane databases were performed for all human studies applying transcriptomic, epigenetic or metabolomic analyses to PA subjects. Studies involving serial analysis of gene expression and microarray, epigenetic studies with methylome analyses and micro-RNA expression profiles, and metabolomic studies focused on improving understanding of the regulation of autonomous aldosterone production in PA were all included. Results: In this review we summarize the main findings in this area and analyze the interplay between primary aldosteronism and several signaling pathways with differential regulation of the RNA and protein expression of several factors involved in, among others, steroidogenesis, calcium signaling, and nuclear, membrane and G-coupled protein receptors. Distinct transcriptomic and metabolomic patterns are also presented herein, depending on the mutational status of APAs. In particular, two partially opposite transcriptional and steroidogenic profiles appear to distinguish APAs carrying a KCNJ5 mutation from all other APAs, which carry different mutations. Conclusions: These findings can substantially contribute to the development of personalized treatment in patients with PA.

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“…Finally, the herein reported GRK2-dependent βAR-AT 1 R crosstalk in AZG cells might not take place at the level of the receptors per se and the signaling of the two receptors could converge at some receptor-proximal downstream effector modulated by GRK2 instead. For instance, the calcium-regulated chloride channel TMEM16A (anoctamine-1), which is activated by calcium/calmodulin-dependent kinase phosphorylation, was very recently implicated in the stimulation of aldosterone production in AZG cells [30,31]. βAR-activated GRK2 may very well phosphorylate and activate this channel, thereby mediating the stimulation of aldosterone secretion by both βARs and AT 1 Rs (AT 1 R elicits intracellular [Ca 2+ ] elevation via G q/11 proteins [23], and Ca 2+ activates TMEM16A).…”

Section: Discussionmentioning

confidence: 99%

GRK2-Mediated Crosstalk Between β-Adrenergic and Angiotensin II Receptors Enhances Adrenocortical Aldosterone Production In Vitro and In Vivo

Pollard

Ghandour

Cora

et al. 2020

IJMS

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Aldosterone is produced by adrenocortical zona glomerulosa (AZG) cells in response to angiotensin II (AngII) acting through its type I receptors (AT1Rs). AT1R is a G protein-coupled receptor (GPCR) that induces aldosterone via both G proteins and the adapter protein βarrestin1, which binds the receptor following its phosphorylation by GPCR-kinases (GRKs) to initiate G protein-independent signaling. β-adrenergic receptors (ARs) also induce aldosterone production in AZG cells. Herein, we investigated whether GRK2 or GRK5, the two major adrenal GRKs, is involved in the catecholaminergic regulation of AngII-dependent aldosterone production. In human AZG (H295R) cells in vitro, the βAR agonist isoproterenol significantly augmented both AngII-dependent aldosterone secretion and synthesis, as measured by the steroidogenic acute regulatory (StAR) protein and CYP11B2 (aldosterone synthase) mRNA inductions. Importantly, GRK2, but not GRK5, was indispensable for the βAR-mediated enhancement of aldosterone in response to AngII. Specifically, GRK2 inhibition with Cmpd101 abolished isoproterenol’s effects on AngII-induced aldosterone synthesis/secretion, whereas the GRK5 knockout via CRISPR/Cas9 had no effect. It is worth noting that these findings were confirmed in vivo, since rats overexpressing GRK2, but not GRK5, in their adrenals had elevated circulating aldosterone levels compared to the control animals. However, treatment with the β-blocker propranolol prevented hyperaldosteronism in the adrenal GRK2-overexpressing rats. In conclusion, GRK2 mediates a βAR-AT1R signaling crosstalk in the adrenal cortex leading to elevated aldosterone production. This suggests that adrenal GRK2 may be a molecular link connecting the sympathetic nervous and renin-angiotensin systems at the level of the adrenal cortex and that its inhibition might be therapeutically advantageous in hyperaldosteronism-related conditions.

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ANO4 (Anoctamin 4) Is a Novel Marker of Zona Glomerulosa That Regulates Stimulated Aldosterone Secretion

Abstract: Supplemental Digital Content is available in the text.

Cited by 18 publications

References 37 publications

Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

Transcriptomics, Epigenetics, and Metabolomics of Primary Aldosteronism

GRK2-Mediated Crosstalk Between β-Adrenergic and Angiotensin II Receptors Enhances Adrenocortical Aldosterone Production In Vitro and In Vivo

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