MLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy

Stephan Lange, Katja Gehmlich, Alexander S. Lun, Jordan Blondelle, Charlotte Hooper, Nancy D. Dalton, Erika A. Alvarez, Xiaoyu Zhang, Marie Louise Bang, Yama A. Abassi, Cristobal G. Dos Remedios, Kirk L. Peterson, Ju Chen, Elisabeth Ehler

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Abstract

MLP (muscle LIM protein)-deficient mice count among the first mouse models for dilated cardiomyopathy (DCM), yet the exact role of MLP in cardiac signalling processes is still enigmatic. Elevated PKCα signalling activity is known to be an important contributor to heart failure. Here we show that MLP directly inhibits the activity of PKCα. In end-stage DCM, PKCα is concentrated at the intercalated disc of cardiomyocytes, where it is sequestered by the adaptor protein CARP in a multiprotein complex together with PLCβ1. In mice deficient for both MLP and CARP the chronic PKCα signalling chain at the intercalated disc is broken and they remain healthy. Our results suggest that the main role of MLP in heart lies in the direct inhibition of PKCα and that chronic uninhibited PKCα activity at the intercalated disc in the absence of functional MLP leads to heart failure.

Original languageEnglish
Article number12120
JournalNature Communications
Volume7
DOIs
Publication statusPublished - Jun 29 2016

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Lange, S., Gehmlich, K., Lun, A. S., Blondelle, J., Hooper, C., Dalton, N. D., Alvarez, E. A., Zhang, X., Bang, M. L., Abassi, Y. A., Dos Remedios, C. G., Peterson, K. L., Chen, J., & Ehler, E. (2016). MLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy. Nature Communications, 7, [12120]. https://doi.org/10.1038/ncomms12120