Mucolipins constitute a family of cation channels with homology with the transient receptor potential family. Mutations in MCOLN1 (mucolipin 1) have been linked to mucolipidosis type IV, a recessive lysosomal storage disease characterized by severe neurological and ophthalmologic abnormalities. At present, little is known about the mechanisms that regulate MCOLN1 activity. In the present paper, we addressed whether MCOLN1 activity is regulated by phosphorylation. We identified two PKA (protein kinase A) consensus motifs in the C-terminal tail of MCOLN1, containing Ser557 and Ser559. Ser557 was the principal phosphorylation site, as mutation of this residue to alanine caused a greater than 75% reduction in the total levels of phosphorylated MCOLN1 C-terminal tail. Activation of PKA with forskolin promoted MCOLN1 phosphorylation, both in vitro and in vivo. In contrast, addition of the PKA inhibitor H89 abolished MCOLN1 phosphorylation. We also found that PKA-mediated phosphorylation regulates MCOLN1 channel activity. Forskolin treatment decreased MCOLN1 channel activity, whereas treatment with H89 increased MCOLN1 channel activity. The stimulatory effect of H89 on MCOLN1 function was not observed when Ser557 and Ser559 were mutated to alanine residues, indicating that these two residues are essential for PKA-mediated negative regulation of MCOLN1. This paper presents the first example of regulation of a member of the mucolipin family by phosphorylation.
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March 2008
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Research Article|
February 12 2008
Mucolipin 1 channel activity is regulated by protein kinase A-mediated phosphorylation
Silvia Vergarajauregui;
Silvia Vergarajauregui
*Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, U.S.A.
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Ross Oberdick;
Ross Oberdick
†Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, U.S.A.
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Kirill Kiselyov;
Kirill Kiselyov
†Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, U.S.A.
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Rosa Puertollano
Rosa Puertollano
1
*Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, U.S.A.
1To whom correspondence should be addressed (email puertolr@mail.nih.gov).
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Publisher: Portland Press Ltd
Received:
May 29 2007
Accepted:
November 07 2007
Accepted Manuscript online:
November 07 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 410 (2): 417–425.
Article history
Received:
May 29 2007
Accepted:
November 07 2007
Accepted Manuscript online:
November 07 2007
Citation
Silvia Vergarajauregui, Ross Oberdick, Kirill Kiselyov, Rosa Puertollano; Mucolipin 1 channel activity is regulated by protein kinase A-mediated phosphorylation. Biochem J 1 March 2008; 410 (2): 417–425. doi: https://doi.org/10.1042/BJ20070713
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