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Agonist-induced Ca2+ entry determined by inositol 1,4,5-trisphosphate recognition
Damian B van Rossum1, Randen L Patterson, Kirill Kiselyov
1Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Summary
Inositol 1,4,5-trisphosphate receptors (IP3R) trigger calcium (Ca2+) entry upon B cell receptor activation, independent of calcium release. IP3 binding, not channel activity, initiates this calcium influx.
Area of Science:
- Cellular Biology
- Immunology
- Biochemistry
Background:
- Calcium (Ca2+) signaling is crucial for B cell activation.
- Inositol 1,4,5-trisphosphate receptors (IP3R) are known regulators of intracellular Ca2+.
- The precise mechanism linking IP3R to agonist-induced Ca2+ entry (ACE) remains debated.
Purpose of the Study:
- To investigate the role of IP3R in mediating Ca2+ entry following B cell receptor activation.
- To determine whether Ca2+ release from the endoplasmic reticulum is essential for ACE.
Main Methods:
- Utilized DT40 B cells lacking IP3R (IP3R-/-).
- Employed IP3R mutants defective in Ca2+ release or IP3 binding.
- Assessed ACE in response to B cell receptor activation.
Main Results:
- ACE was restored in IP3R-/- cells expressing IP3R mutants with impaired Ca2+ release channels.
- ACE could not be rescued by IP3R mutants lacking IP3 binding capacity.
- These findings demonstrate IP3R-dependent ACE independent of Ca2+ release.
Conclusions:
- IP3 binding to IP3R, not Ca2+ release, is the critical trigger for ACE.
- Agonist-induced Ca2+ entry is regulated by an IP3-dependent conformational change in IP3R.
- This mechanism highlights a novel role for IP3R in B cell signaling.