Caldendrin, a neuron-specific modulator of Cav/1.2 (L-type) Ca2+ channels.
EF-hand Ca2+-binding proteins such as calmodulin and CaBP1 have emerged as important regulatory subunits of voltage-gated Ca2+ channels. Here, we show that caldendrin, a variant of CaBP1 enriched in the brain, interacts with and distinctly modulates Cav1.2 (L-type) voltage-gated Ca2+ channels relative to other Ca2+-binding proteins. Caldendrin binds to the C-terminal IQ-domain of the pore-forming alpha1-subunit of Cav1.2 (alpha(1)1.2) and competitively displaces calmodulin and CaBP1 from this site. Compared with CaBP1, caldendrin causes a more modest suppression of Ca2+-dependent inactivation of Cav1.2 through a different subset of molecular determinants. Caldendrin does not bind to the N-terminal domain of alpha11.2, a site that is critical for functional interactions of the channel with CaBP1. Deletion of the N-terminal domain inhibits CaBP1, but spares caldendrin modulation of Cav1.2 inactivation. In contrast, mutations of the IQ-domain abolish physical and functional interactions of caldendrin and Cav1.2, but do not prevent channel modulation by CaBP1. Using antibodies specific for caldendrin and Cav1.2, we show that caldendrin coimmunoprecipitates with Cav1.2 from the brain and colocalizes with Cav1.2 in somatodendritic puncta of cortical neurons in culture. Our findings reveal functional diversity within related Ca2+-binding proteins, which may enhance the specificity of Ca2+ signaling by Cav1.2 channels in different cellular contexts.
Tippens
Alyssa L
AL
Department of Pharmacology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Lee
Amy
A
D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D003713:Dendritic Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors
D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; C419385:L-type calcium channel alpha(1C); C085577:Ca2+-binding protein-1; D002118:Calcium