Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the β2 adrenergic receptor

Tommaso Patriarchi, Hai Qian, Valentina Di Biase, Zulfiquar A. Malik, Dhrubajyoti Chowdhury, Jennifer L. Price, Erik A. Hammes, Olivia R. Buonarati, Ruth E. Westenbroek, William A. Catterall, Franz Hofmann, Yang Kevin Xiang, Geoffrey G. Murphy, Chao Ye Chen, Manuel F Navedo, Johannes W Hell

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Agonist-triggered downregulation of β-adrenergic receptors (ARs) constitutes vital negative feedback to prevent cellular overexcitation. Here, we report a novel downregulation of β2AR signaling highly specific for Cav1.2. We find that β2-AR binding to Cav1.2 residues 1923–1942 is required for β-adrenergic regulation of Cav1.2. Despite the prominence of PKA-mediated phosphorylation of Cav1.2 S1928 within the newly identified β2AR binding site, its physiological function has so far escaped identification. We show that phosphorylation of S1928 displaces the β2AR from Cav1.2 upon β-adrenergic stimulation rendering Cav1.2 refractory for several minutes from further β-adrenergic stimulation. This effect is lost in S1928A knock-in mice. Although AMPARs are clustered at postsynaptic sites like Cav1.2, β2AR association with and regulation of AMPARs do not show such dissociation. Accordingly, displacement of the β2AR from Cav1.2 is a uniquely specific desensitization mechanism of Cav1.2 regulation by highly localized β2AR/cAMP/PKA/S1928 signaling. The physiological implications of this mechanism are underscored by our finding that LTP induced by prolonged theta tetanus (PTT-LTP) depends on Cav1.2 and its regulation by channel-associated β2AR.

Original languageEnglish (US)
Pages (from-to)1330-1345
Number of pages16
JournalEMBO Journal
Volume35
Issue number12
DOIs
StatePublished - Jun 15 2016

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Phosphorylation
Adrenergic Agents
Adrenergic Receptors
Down-Regulation
Tetanus
Refractory materials
Binding Sites
Association reactions
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Keywords

  • adrenergic receptors
  • glutamate receptors
  • L-type calcium channels
  • protein kinase A

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Cite this

Patriarchi, T., Qian, H., Di Biase, V., Malik, Z. A., Chowdhury, D., Price, J. L., ... Hell, J. W. (2016). Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the β2 adrenergic receptor. EMBO Journal, 35(12), 1330-1345. https://doi.org/10.15252/embj.201593409

Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the β2 adrenergic receptor. / Patriarchi, Tommaso; Qian, Hai; Di Biase, Valentina; Malik, Zulfiquar A.; Chowdhury, Dhrubajyoti; Price, Jennifer L.; Hammes, Erik A.; Buonarati, Olivia R.; Westenbroek, Ruth E.; Catterall, William A.; Hofmann, Franz; Xiang, Yang Kevin; Murphy, Geoffrey G.; Chen, Chao Ye; Navedo, Manuel F; Hell, Johannes W.

In: EMBO Journal, Vol. 35, No. 12, 15.06.2016, p. 1330-1345.

Research output: Contribution to journalArticle

Patriarchi, T, Qian, H, Di Biase, V, Malik, ZA, Chowdhury, D, Price, JL, Hammes, EA, Buonarati, OR, Westenbroek, RE, Catterall, WA, Hofmann, F, Xiang, YK, Murphy, GG, Chen, CY, Navedo, MF & Hell, JW 2016, 'Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the β2 adrenergic receptor', EMBO Journal, vol. 35, no. 12, pp. 1330-1345. https://doi.org/10.15252/embj.201593409
Patriarchi T, Qian H, Di Biase V, Malik ZA, Chowdhury D, Price JL et al. Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the β2 adrenergic receptor. EMBO Journal. 2016 Jun 15;35(12):1330-1345. https://doi.org/10.15252/embj.201593409
Patriarchi, Tommaso ; Qian, Hai ; Di Biase, Valentina ; Malik, Zulfiquar A. ; Chowdhury, Dhrubajyoti ; Price, Jennifer L. ; Hammes, Erik A. ; Buonarati, Olivia R. ; Westenbroek, Ruth E. ; Catterall, William A. ; Hofmann, Franz ; Xiang, Yang Kevin ; Murphy, Geoffrey G. ; Chen, Chao Ye ; Navedo, Manuel F ; Hell, Johannes W. / Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the β2 adrenergic receptor. In: EMBO Journal. 2016 ; Vol. 35, No. 12. pp. 1330-1345.
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AU - Qian, Hai

AU - Di Biase, Valentina

AU - Malik, Zulfiquar A.

AU - Chowdhury, Dhrubajyoti

AU - Price, Jennifer L.

AU - Hammes, Erik A.

AU - Buonarati, Olivia R.

AU - Westenbroek, Ruth E.

AU - Catterall, William A.

AU - Hofmann, Franz

AU - Xiang, Yang Kevin

AU - Murphy, Geoffrey G.

AU - Chen, Chao Ye

AU - Navedo, Manuel F

AU - Hell, Johannes W

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