Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-3

Abstract N-type voltage-gated calcium channels (CaV2.2) are predominantly expressed at presynaptic terminals, and their function is regulated by auxiliary α2δ and β subunits. All four mammalian α2δ subunits enhance calcium currents through CaV1 and CaV2 channels, and this increase is attributed, in...

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Autores principales:	James O. Meyer, Annette C. Dolphin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/505d687843834437b5e5ce83ac45051f
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spelling	oai:doaj.org-article:505d687843834437b5e5ce83ac45051f2021-12-02T17:16:05ZRab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-310.1038/s41598-021-89820-12045-2322https://doaj.org/article/505d687843834437b5e5ce83ac45051f2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89820-1https://doaj.org/toc/2045-2322Abstract N-type voltage-gated calcium channels (CaV2.2) are predominantly expressed at presynaptic terminals, and their function is regulated by auxiliary α2δ and β subunits. All four mammalian α2δ subunits enhance calcium currents through CaV1 and CaV2 channels, and this increase is attributed, in part, to increased CaV expression at the plasma membrane. In the present study we provide evidence that α2δ-1, like α2δ-2, is recycled to the plasma membrane through a Rab11a-dependent endosomal recycling pathway. Using a dominant-negative Rab11a mutant, Rab11a(S25N), we show that α2δ-1 increases plasma membrane CaV2.2 expression by increasing the rate and extent of net forward CaV2.2 trafficking in a Rab11a-dependent manner. Dominant-negative Rab11a also reduces the ability of α2δ-1 to increase CaV2.2 expression on the cell-surface of hippocampal neurites. In contrast, α2δ-3 does not enhance rapid forward CaV2.2 trafficking, regardless of whether Rab11a(S25N) is present. In addition, whole-cell CaV2.2 currents are reduced by co-expression of Rab11a(S25N) in the presence of α2δ-1, but not α2δ-3. Taken together these data suggest that α2δ subtypes participate in distinct trafficking pathways which in turn influence the localisation and function of CaV2.2.James O. MeyerAnnette C. DolphinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q James O. Meyer Annette C. Dolphin Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-3
description	Abstract N-type voltage-gated calcium channels (CaV2.2) are predominantly expressed at presynaptic terminals, and their function is regulated by auxiliary α2δ and β subunits. All four mammalian α2δ subunits enhance calcium currents through CaV1 and CaV2 channels, and this increase is attributed, in part, to increased CaV expression at the plasma membrane. In the present study we provide evidence that α2δ-1, like α2δ-2, is recycled to the plasma membrane through a Rab11a-dependent endosomal recycling pathway. Using a dominant-negative Rab11a mutant, Rab11a(S25N), we show that α2δ-1 increases plasma membrane CaV2.2 expression by increasing the rate and extent of net forward CaV2.2 trafficking in a Rab11a-dependent manner. Dominant-negative Rab11a also reduces the ability of α2δ-1 to increase CaV2.2 expression on the cell-surface of hippocampal neurites. In contrast, α2δ-3 does not enhance rapid forward CaV2.2 trafficking, regardless of whether Rab11a(S25N) is present. In addition, whole-cell CaV2.2 currents are reduced by co-expression of Rab11a(S25N) in the presence of α2δ-1, but not α2δ-3. Taken together these data suggest that α2δ subtypes participate in distinct trafficking pathways which in turn influence the localisation and function of CaV2.2.
format	article
author	James O. Meyer Annette C. Dolphin
author_facet	James O. Meyer Annette C. Dolphin
author_sort	James O. Meyer
title	Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-3
title_short	Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-3
title_full	Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-3
title_fullStr	Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-3
title_full_unstemmed	Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-3
title_sort	rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-3
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/505d687843834437b5e5ce83ac45051f
work_keys_str_mv	AT jamesomeyer rab11dependentrecyclingofcalciumchannelsismediatedbyauxiliarysubunita2d1butnota2d3 AT annettecdolphin rab11dependentrecyclingofcalciumchannelsismediatedbyauxiliarysubunita2d1butnota2d3
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Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-3

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