Agonist-Induced Ca2+Entry Determined by Inositol 1,4,5-Trisphosphate Recognition

It has been considered that Ca2+release is the causal trigger for Ca2+entry after receptor activation. In DT40 B cells devoid of inositol 1,4,5-trisphosphate receptors ( IP3R), the lack of Ca2+entry in response to receptor activation is attributed to the absence of Ca2+release. We reveal in this art...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-02, Vol.101 (8), p.2323-2327
Main Authors: van Rossum, Damian B., Patterson, Randen L., Kiselyov, Kirill, Boehning, Darren, Barrow, Roxanne K., Gill, Donald L., Snyder, Solomon H.
Format: Article
Language:English
Subjects:
Agonists
Amino Acid Substitution
Animals
B lymphocytes
Biological Sciences
Biological Transport
Calcium - metabolism
Calcium Channels - chemistry
Calcium Channels - deficiency
Calcium Channels - genetics
Calcium Channels - physiology
Calcium Signaling - physiology
Cell cycle
Cell lines
Cellular biology
Endoplasmic reticulum
Endoplasmic Reticulum - metabolism
HEK293 cells
Hormones
Inositol 1
Inositol 1,4,5-Trisphosphate - physiology
Inositol 1,4,5-Trisphosphate Receptors
Inositols
Kidneys
Kinetics
Mutagenesis, Site-Directed
PC12 Cells
Rats
Receptors
Receptors, Cytoplasmic and Nuclear - chemistry
Receptors, Cytoplasmic and Nuclear - deficiency
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, Cytoplasmic and Nuclear - physiology
Recombinant Proteins - metabolism
Transfection
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Summary:It has been considered that Ca2+release is the causal trigger for Ca2+entry after receptor activation. In DT40 B cells devoid of inositol 1,4,5-trisphosphate receptors ( IP3R), the lack of Ca2+entry in response to receptor activation is attributed to the absence of Ca2+release. We reveal in this article that IP3R recognition of IP3determines agonist-induced Ca2+entry (ACE), independent of its Ca2+release activity. In DT40 IP3R-/-cells, endogenous ACE can be rescued with type 1 IP3R mutants (both a ΔC-terminal truncation mutant and a D2550A pore mutant), which are defective in Ca2+release channel activity. Thus, in response to B cell receptor activation, ACE is restored in an IP3R-dependent manner without Ca2+store release. Conversely, ACE cannot be rescued with mutant IP3Rs lacking IP3binding (both the Δ90-110 and R265Q IP3-binding site mutants). We conclude that an IP3-dependent conformational change in the IP3R, not endoplasmic reticulum Ca2+pool release, triggers ACE.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0308565100