Regulation of aldosterone secretion by Ca v 1.3

Catherine B. Xie; Lalarukh Haris Shaikh; Sumedha Garg; Gizem Tanriver; Ada E.D. Teo; Junhua Zhou; Carmela Maniero; Wanfeng Zhao; Soosung Kang; Richard B. Silverman; Elena A.B. Azizan; Morris J. Brown

doi:10.1038/srep24697

Regulation of aldosterone secretion by Ca v 1.3

Catherine B. Xie, Lalarukh Haris Shaikh, Sumedha Garg, Gizem Tanriver, Ada E.D. Teo, Junhua Zhou, Carmela Maniero, Wanfeng Zhao, Soosung Kang, Richard B. Silverman, Elena A.B. Azizan, Morris J. Brown

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

Aldosterone-producing adenomas (APAs) vary in phenotype and genotype. Zona glomerulosa (ZG)-like APAs frequently have mutations of an L-type calcium channel (LTCC) Ca V 1.3. Using a novel antagonist of Ca V 1.3, compound 8, we investigated the role of Ca V 1.3 on steroidogenesis in the human adrenocortical cell line, H295R, and in primary human adrenal cells. This investigational drug was compared with the common antihypertensive drug nifedipine, which has 4.5-fold selectivity for the vascular LTCC, Ca V 1.2, over Ca V 1.3. In H295R cells transfected with wild-type or mutant Ca V 1.3 channels, the latter produced more aldosterone than wild-type, which was ameliorated by 100 1/4M of compound 8. In primary adrenal and non-transfected H295R cells, compound 8 decreased aldosterone production similar to high concentration of nifedipine (100 1/4M). Selective Ca V 1.3 blockade may offer a novel way of treating primary hyperaldosteronism, which avoids the vascular side effects of Ca V 1.2-blockade, and provides targeted treatment for ZG-like APAs with mutations of Ca V 1.3.

Original language	English
Article number	24697
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep24697
State	Published - 21 Apr 2016

Bibliographical note

Funding Information:
This work is supported by NIHR Senior Investigator grant NF-SI-051210052 awarded to M.J.B.; the Austin Doyle Award (Servier Australia) and the Tunku Abdul Rahman Centenary Fund (St Catharines College, Cambridge, UK) awarded to E.A.B.A.; Gates Cambridge Scholarship awarded to C.B.X.; L.H.S., S.G. and C.M. are supported by the British Heart Foundation PhD studentship FS/11/35/28871, FS/14/75/31134 and FS/14/12/30540 respectively; J.Z. was supported by the Cambridge Overseas Trust Scholarship and the Sun Hung Kai Properties-Kwoks Foundation; A.E.D.T. is funded by the Agency for Science, Technology & Research (A∗STAR) Singapore and Wellcome Trust Award 085686/Z/08/A; LHS, JZ and EABA were further supported by the NIHR Cambridge Biomedical Research Centre; the Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. The CaV1.3 constructs were kindly gifted by Dr. Joerg Striessnig and Dr Petronel Tuluc.

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@article{24df865bd8fb40c6be80f419148d4445,

title = "Regulation of aldosterone secretion by Ca v 1.3",

abstract = "Aldosterone-producing adenomas (APAs) vary in phenotype and genotype. Zona glomerulosa (ZG)-like APAs frequently have mutations of an L-type calcium channel (LTCC) Ca V 1.3. Using a novel antagonist of Ca V 1.3, compound 8, we investigated the role of Ca V 1.3 on steroidogenesis in the human adrenocortical cell line, H295R, and in primary human adrenal cells. This investigational drug was compared with the common antihypertensive drug nifedipine, which has 4.5-fold selectivity for the vascular LTCC, Ca V 1.2, over Ca V 1.3. In H295R cells transfected with wild-type or mutant Ca V 1.3 channels, the latter produced more aldosterone than wild-type, which was ameliorated by 100 1/4M of compound 8. In primary adrenal and non-transfected H295R cells, compound 8 decreased aldosterone production similar to high concentration of nifedipine (100 1/4M). Selective Ca V 1.3 blockade may offer a novel way of treating primary hyperaldosteronism, which avoids the vascular side effects of Ca V 1.2-blockade, and provides targeted treatment for ZG-like APAs with mutations of Ca V 1.3.",

author = "Xie, {Catherine B.} and {Haris Shaikh}, Lalarukh and Sumedha Garg and Gizem Tanriver and Teo, {Ada E.D.} and Junhua Zhou and Carmela Maniero and Wanfeng Zhao and Soosung Kang and Silverman, {Richard B.} and Azizan, {Elena A.B.} and Brown, {Morris J.}",

note = "Funding Information: This work is supported by NIHR Senior Investigator grant NF-SI-051210052 awarded to M.J.B.; the Austin Doyle Award (Servier Australia) and the Tunku Abdul Rahman Centenary Fund (St Catharines College, Cambridge, UK) awarded to E.A.B.A.; Gates Cambridge Scholarship awarded to C.B.X.; L.H.S., S.G. and C.M. are supported by the British Heart Foundation PhD studentship FS/11/35/28871, FS/14/75/31134 and FS/14/12/30540 respectively; J.Z. was supported by the Cambridge Overseas Trust Scholarship and the Sun Hung Kai Properties-Kwoks Foundation; A.E.D.T. is funded by the Agency for Science, Technology & Research (A∗STAR) Singapore and Wellcome Trust Award 085686/Z/08/A; LHS, JZ and EABA were further supported by the NIHR Cambridge Biomedical Research Centre; the Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. The CaV1.3 constructs were kindly gifted by Dr. Joerg Striessnig and Dr Petronel Tuluc.",

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doi = "10.1038/srep24697",

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AU - Haris Shaikh, Lalarukh

AU - Garg, Sumedha

AU - Tanriver, Gizem

AU - Teo, Ada E.D.

AU - Zhou, Junhua

AU - Maniero, Carmela

AU - Zhao, Wanfeng

AU - Kang, Soosung

AU - Silverman, Richard B.

AU - Azizan, Elena A.B.

AU - Brown, Morris J.

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Y1 - 2016/4/21

N2 - Aldosterone-producing adenomas (APAs) vary in phenotype and genotype. Zona glomerulosa (ZG)-like APAs frequently have mutations of an L-type calcium channel (LTCC) Ca V 1.3. Using a novel antagonist of Ca V 1.3, compound 8, we investigated the role of Ca V 1.3 on steroidogenesis in the human adrenocortical cell line, H295R, and in primary human adrenal cells. This investigational drug was compared with the common antihypertensive drug nifedipine, which has 4.5-fold selectivity for the vascular LTCC, Ca V 1.2, over Ca V 1.3. In H295R cells transfected with wild-type or mutant Ca V 1.3 channels, the latter produced more aldosterone than wild-type, which was ameliorated by 100 1/4M of compound 8. In primary adrenal and non-transfected H295R cells, compound 8 decreased aldosterone production similar to high concentration of nifedipine (100 1/4M). Selective Ca V 1.3 blockade may offer a novel way of treating primary hyperaldosteronism, which avoids the vascular side effects of Ca V 1.2-blockade, and provides targeted treatment for ZG-like APAs with mutations of Ca V 1.3.

AB - Aldosterone-producing adenomas (APAs) vary in phenotype and genotype. Zona glomerulosa (ZG)-like APAs frequently have mutations of an L-type calcium channel (LTCC) Ca V 1.3. Using a novel antagonist of Ca V 1.3, compound 8, we investigated the role of Ca V 1.3 on steroidogenesis in the human adrenocortical cell line, H295R, and in primary human adrenal cells. This investigational drug was compared with the common antihypertensive drug nifedipine, which has 4.5-fold selectivity for the vascular LTCC, Ca V 1.2, over Ca V 1.3. In H295R cells transfected with wild-type or mutant Ca V 1.3 channels, the latter produced more aldosterone than wild-type, which was ameliorated by 100 1/4M of compound 8. In primary adrenal and non-transfected H295R cells, compound 8 decreased aldosterone production similar to high concentration of nifedipine (100 1/4M). Selective Ca V 1.3 blockade may offer a novel way of treating primary hyperaldosteronism, which avoids the vascular side effects of Ca V 1.2-blockade, and provides targeted treatment for ZG-like APAs with mutations of Ca V 1.3.

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Regulation of aldosterone secretion by Ca v 1.3

Abstract

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