Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells.

Recently, we reported that the chemokine (C-X-C motif) receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) heteromerize with α1A/B/D-adrenoceptors (ARs) and arginine vasopressin receptor 1A (AVPR1A) in recombinant systems and in rodent and human vascular smooth muscle cells (hVSMCs). In the...

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Autores principales:	Lauren J Albee, Xianlong Gao, Matthias Majetschak
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a737bd5cbffa44ffa105dd066ea4bfa9
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spelling	oai:doaj.org-article:a737bd5cbffa44ffa105dd066ea4bfa92021-12-02T20:10:03ZPlasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells.1932-620310.1371/journal.pone.0253821https://doaj.org/article/a737bd5cbffa44ffa105dd066ea4bfa92021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0253821https://doaj.org/toc/1932-6203Recently, we reported that the chemokine (C-X-C motif) receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) heteromerize with α1A/B/D-adrenoceptors (ARs) and arginine vasopressin receptor 1A (AVPR1A) in recombinant systems and in rodent and human vascular smooth muscle cells (hVSMCs). In these studies, we observed that heteromerization between two receptor partners may depend on the presence and the expression levels of other partnering receptors. To test this hypothesis and to gain initial insight into the formation of these receptor heteromers in native cells, we utilized proximity ligation assays in hVSMCs to visualize receptor-receptor proximity and systematically studied how manipulation of the expression levels of individual protomers affect heteromerization patterns among other interacting receptor partners. We confirmed subtype-specific heteromerization between endogenously expressed α1A/B/D-ARs and detected that AVPR1A also heteromerizes with α1A/B/D-ARs. siRNA knockdown of CXCR4 and of ACKR3 resulted in a significant re-arrangement of the heteromerization patterns among α1-AR subtypes. Similarly, siRNA knockdown of AVPR1A significantly increased heteromerization signals for seven of the ten receptor pairs between CXCR4, ACKR3, and α1A/B/D-ARs. Our findings suggest plasticity of seven transmembrane helix (7TM) receptor heteromerization in native cells and could be explained by a supramolecular organization of these receptors within dynamic clusters in the plasma membrane. Because we previously observed that recombinant CXCR4, ACKR3, α1a-AR and AVPR1A form hetero-oligomeric complexes composed of 2-4 different protomers, which show signaling properties distinct from individual protomers, re-arrangements of receptor heteromerization patterns in native cells may contribute to the phenomenon of context-dependent GPCR signaling. Furthermore, these findings advise caution in the interpretation of functional consequences after 7TM receptor knockdown in experimental models. Alterations of the heteromerization patterns among other receptor partners may alter physiological and pathological responses, in particular in more complex systems, such as studies on the function of isolated organs or in in vivo experiments.Lauren J AlbeeXianlong GaoMatthias MajetschakPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0253821 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lauren J Albee Xianlong Gao Matthias Majetschak Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells.
description	Recently, we reported that the chemokine (C-X-C motif) receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) heteromerize with α1A/B/D-adrenoceptors (ARs) and arginine vasopressin receptor 1A (AVPR1A) in recombinant systems and in rodent and human vascular smooth muscle cells (hVSMCs). In these studies, we observed that heteromerization between two receptor partners may depend on the presence and the expression levels of other partnering receptors. To test this hypothesis and to gain initial insight into the formation of these receptor heteromers in native cells, we utilized proximity ligation assays in hVSMCs to visualize receptor-receptor proximity and systematically studied how manipulation of the expression levels of individual protomers affect heteromerization patterns among other interacting receptor partners. We confirmed subtype-specific heteromerization between endogenously expressed α1A/B/D-ARs and detected that AVPR1A also heteromerizes with α1A/B/D-ARs. siRNA knockdown of CXCR4 and of ACKR3 resulted in a significant re-arrangement of the heteromerization patterns among α1-AR subtypes. Similarly, siRNA knockdown of AVPR1A significantly increased heteromerization signals for seven of the ten receptor pairs between CXCR4, ACKR3, and α1A/B/D-ARs. Our findings suggest plasticity of seven transmembrane helix (7TM) receptor heteromerization in native cells and could be explained by a supramolecular organization of these receptors within dynamic clusters in the plasma membrane. Because we previously observed that recombinant CXCR4, ACKR3, α1a-AR and AVPR1A form hetero-oligomeric complexes composed of 2-4 different protomers, which show signaling properties distinct from individual protomers, re-arrangements of receptor heteromerization patterns in native cells may contribute to the phenomenon of context-dependent GPCR signaling. Furthermore, these findings advise caution in the interpretation of functional consequences after 7TM receptor knockdown in experimental models. Alterations of the heteromerization patterns among other receptor partners may alter physiological and pathological responses, in particular in more complex systems, such as studies on the function of isolated organs or in in vivo experiments.
format	article
author	Lauren J Albee Xianlong Gao Matthias Majetschak
author_facet	Lauren J Albee Xianlong Gao Matthias Majetschak
author_sort	Lauren J Albee
title	Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells.
title_short	Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells.
title_full	Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells.
title_fullStr	Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells.
title_full_unstemmed	Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells.
title_sort	plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/a737bd5cbffa44ffa105dd066ea4bfa9
work_keys_str_mv	AT laurenjalbee plasticityofseventransmembranehelixreceptorheteromersinhumanvascularsmoothmusclecells AT xianlonggao plasticityofseventransmembranehelixreceptorheteromersinhumanvascularsmoothmusclecells AT matthiasmajetschak plasticityofseventransmembranehelixreceptorheteromersinhumanvascularsmoothmusclecells
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Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells.

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