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Splice-variant-specific effects of primary aldosteronism point mutations on human CaV3.2 calcium channels.
Cell Calcium 2019; 84:102104CC

Abstract

CaV3.2 calcium channels play important roles in both neural excitability and aldosterone secretion. Recent clinical studies found four germline mutations (S196 L, M1549I, V1951E and P2083 L) in CaV3.2 channels. All four mutations caused primary aldosteronism (PA), while only the M1549I mutation resulted in obvious neural malfunctions besides PA. In human, there are two major CaV3.2 channel gene (CACNA1H) splice variants, either with or without exon 26. In this study, we tested the expression of the two CACNA1H splice variants in zona glomerulosa (ZG) cells of human adrenal cortex and the possibility that CaV3.2 (-26) and CaV3.2 (+26) channels have different functional responses to the four PA mutations. We found that human ZG cells only express long form CaV3.2(+26) channels. The M1549I mutation slowed the inactivation of CaV3.2(+26) more than 5 fold, and CaV3.2(-26) more than 2 fold. The S196 L, V1951E and P2083 L mutations accelerated channel recovery from inactivation for CaV3.2(+26), but not CaV3.2(-26) channels. All four mutations resulted in gain of function of CaV3.2(+26) channels, leading to overproduction of aldosterone. In conclusion, the four PA mutations caused more profound changes on CaV3.2 (+26) currents than on CaV3.2 (-26) currents, and except the M1549I mutation, the S196 L, V1951E and P2083 L have little effect on the electrophysiological properties of CaV3.2(-26) currents, which may partially explain the limitation of the phenotype associated with the V1951E, S196 L and P2083 L germline mutations to PA.

Authors+Show Affiliations

Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science, Fudan University, Shanghai, China.Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science, Fudan University, Shanghai, China.Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science, Fudan University, Shanghai, China.Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: clhu@fudan.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31706065

Citation

He, Min, et al. "Splice-variant-specific Effects of Primary Aldosteronism Point Mutations On Human CaV3.2 Calcium Channels." Cell Calcium, vol. 84, 2019, p. 102104.
He M, Xu Z, Zhang Y, et al. Splice-variant-specific effects of primary aldosteronism point mutations on human CaV3.2 calcium channels. Cell Calcium. 2019;84:102104.
He, M., Xu, Z., Zhang, Y., & Hu, C. (2019). Splice-variant-specific effects of primary aldosteronism point mutations on human CaV3.2 calcium channels. Cell Calcium, 84, p. 102104. doi:10.1016/j.ceca.2019.102104.
He M, et al. Splice-variant-specific Effects of Primary Aldosteronism Point Mutations On Human CaV3.2 Calcium Channels. Cell Calcium. 2019;84:102104. PubMed PMID: 31706065.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Splice-variant-specific effects of primary aldosteronism point mutations on human CaV3.2 calcium channels. AU - He,Min, AU - Xu,Zilan, AU - Zhang,Yuchen, AU - Hu,Changlong, Y1 - 2019/11/01/ PY - 2019/07/15/received PY - 2019/09/02/revised PY - 2019/09/08/accepted PY - 2019/11/11/pubmed PY - 2019/11/11/medline PY - 2019/11/10/entrez KW - Ca(V)3.2 calcium channels KW - Primary aldosteronism mutations KW - Splice-variant-specific effects SP - 102104 EP - 102104 JF - Cell calcium JO - Cell Calcium VL - 84 N2 - CaV3.2 calcium channels play important roles in both neural excitability and aldosterone secretion. Recent clinical studies found four germline mutations (S196 L, M1549I, V1951E and P2083 L) in CaV3.2 channels. All four mutations caused primary aldosteronism (PA), while only the M1549I mutation resulted in obvious neural malfunctions besides PA. In human, there are two major CaV3.2 channel gene (CACNA1H) splice variants, either with or without exon 26. In this study, we tested the expression of the two CACNA1H splice variants in zona glomerulosa (ZG) cells of human adrenal cortex and the possibility that CaV3.2 (-26) and CaV3.2 (+26) channels have different functional responses to the four PA mutations. We found that human ZG cells only express long form CaV3.2(+26) channels. The M1549I mutation slowed the inactivation of CaV3.2(+26) more than 5 fold, and CaV3.2(-26) more than 2 fold. The S196 L, V1951E and P2083 L mutations accelerated channel recovery from inactivation for CaV3.2(+26), but not CaV3.2(-26) channels. All four mutations resulted in gain of function of CaV3.2(+26) channels, leading to overproduction of aldosterone. In conclusion, the four PA mutations caused more profound changes on CaV3.2 (+26) currents than on CaV3.2 (-26) currents, and except the M1549I mutation, the S196 L, V1951E and P2083 L have little effect on the electrophysiological properties of CaV3.2(-26) currents, which may partially explain the limitation of the phenotype associated with the V1951E, S196 L and P2083 L germline mutations to PA. SN - 1532-1991 UR - https://www.unboundmedicine.com/medline/citation/31706065/Splice-variant-specific_effects_of_primary_aldosteronism_point_mutations_on_human_CaV3.2_calcium_channels L2 - https://linkinghub.elsevier.com/retrieve/pii/S0143-4160(19)30171-X DB - PRIME DP - Unbound Medicine ER -