Calmodulin Mediates Calcium-Dependent Inactivation of the Cerebellar Type 1 Inositol 1,4,5-Trisphosphate Receptor

Michikawa, Takayuki; Hirota, Junji; Kawano, Seiko; Hiraoka, Masayasu; Yamada, Maki K.; Furuichi, Teiichi; Mikoshiba, Katsuhiko

doi:10.1016/s0896-6273(01)80037-4

Cited by 158 publications

(137 citation statements)

References 60 publications

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“…The effect of CaM could be due to inhibition of IP 3 R opening, which has been reported in some systems (39)(40)(41), although there is currently no agreement about the mechanism of action of CaM on IP 3 Rs (42). Irrespective of the mechanism of action, the protective effect of CaM on the granular store is of considerable interest, particularly in view of data showing that the physiological local Ca 2+ spikes in the granular region elicited by hormonal stimulation recruit CaM from the basolateral cytoplasm to the granular region (20).…”

Section: Discussionmentioning

confidence: 69%

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Gerasimenko

Lür

Ferdek

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Alcohol abuse is a major global health problem, but there is still much uncertainty about the mechanisms of action. So far, the effects of ethanol on ion channels in the plasma membrane have received the most attention. We have now investigated actions on intracellular calcium channels in pancreatic acinar cells. Our aim was to discover the mechanism by which alcohol influences calcium homeostasis and thereby understand how alcohol can trigger premature intracellular trypsinogen activation, which is the initiating step for alcohol-induced pancreatitis. We used intact or twophoton permeabilized acinar cells isolated from wild-type mice or mice in which inositol trisphosphate receptors of type 2 or types 2 and 3 were knocked out. In permeabilized pancreatic acinar cells even a relatively low ethanol concentration elicited calcium release from intracellular stores and intracellular trypsinogen activation. The calcium sensor calmodulin (at a normal intracellular concentration) markedly reduced ethanol-induced calcium release and trypsinogen activation in permeabilized cells, effects prevented by the calmodulin inhibitor peptide. A calmodulin activator virtually abolished the modest ethanol effects in intact cells. Both ethanol-elicited calcium liberation and trypsinogen activation were significantly reduced in cells from type 2 inositol trisphosphate receptor knockout mice. More profound reductions were seen in cells from double inositol trisphosphate receptor (types 2 and 3) knockout mice. The inositol trisphosphate receptors, required for normal pancreatic stimulus-secretion coupling, are also responsible for the toxic ethanol action. Calmodulin protects by reducing calcium release sensitivity.

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Section: Discussionmentioning

confidence: 69%

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Gerasimenko

Lür

Ferdek

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Permeabilized cells were gently washed with the internal solution containing 5 mM EGTA. Free Ca 2+ concentrations in the internal solutions were adjusted with K 2 HEDTA and CaHEDTA at 37°C according to the described method (28). Fluorescent signals were acquired with an IX-71 or IX-81 inverted microscope (Olympus), a cooled CCD camera ORCA-ER (Hamamatsu Photonics), and a 40× (n. a., 1.35) objective lens (Olympus), as described (34).…”

Section: Methodsmentioning

confidence: 99%

Mechanistic basis of bell-shaped dependence of inositol 1,4,5-trisphosphate receptor gating on cytosolic calcium

Shinohara

Michikawa

Enomoto

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R) is an intracellular Ca 2+ release channel, and its opening is controlled by IP 3 and Ca 2+ . A single IP 3 binding site and multiple Ca 2+ binding sites exist on single subunits, but the precise nature of the interplay between these two ligands in regulating biphasic dependence of channel activity on cytosolic Ca 2+ is unknown. In this study, we visualized conformational changes in IP 3 R evoked by various concentrations of ligands by using the FRET between two fluorescent proteins fused to the N terminus of individual subunits. IP 3 and Ca 2+ have opposite effects on the FRET signal change, but the combined effect of these ligands is not a simple summative response. The bell-shaped Ca 2+ dependence of FRET efficiency was observed after the subtraction of the component corresponding to the FRET change evoked by Ca 2+ alone from the FRET changes evoked by both ligands together. A mutant IP 3 R containing a single amino acid substitution at K508, which is critical for IP 3 binding, did not exhibit this bell-shaped Ca 2+ dependence of the subtracted FRET efficiency. Mutation at E2100, which is known as a Ca 2+ sensor, resulted in w10-fold reduction in the Ca 2+ dependence of the subtracted signal. These results suggest that the subtracted FRET signal reflects IP 3 R activity. We propose a five-state model, which implements a dual-ligand competition response without complex allosteric regulation of Ca 2+ binding affinity, as the mechanism underlying the IP 3 -dependent regulation of the bell-shaped relationship between the IP 3 R activity and cytosolic Ca 2+ .calcium signal | channel gating | ion channel T he inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R) is a dualligand-gated Ca 2+ release channel whose opening is controlled by IP 3 and Ca 2+ (1) and which plays a crucial role in the generation of Ca 2+ signals that control numerous cellular processes (2). Individual IP 3 R subunits possess a single IP 3 binding site (3) and multiple Ca 2+ binding sites (4, 5), and tetrameric complexes of these subunits form functional IP 3 -gated Ca 2+ release channels (6). Cytoplasmic Ca 2+ regulates IP 3 R in a biphasic manner: Ca 2+ release is potentiated at low Ca 2+ concentrations but inhibited at higher Ca 2+ concentrations (7,8). The stimulatory effect suggests that the channels display the process of Ca 2+ -induced Ca 2+ release, which underlies Ca 2+ spike generation and wave propagation. In other words, the bell-shaped dependence on cytosolic Ca 2+ is the fundamental property of IP 3 R for the generation of Ca 2+ excitability (9).IP 3 monotonically activates the IP 3 R channels at constant Ca 2+ concentrations (10), but IP 3 dynamically changes the Ca 2+ sensitivity of the channel (11,12). At subsaturating concentrations of IP 3 , the optimal Ca 2+ concentration for IP 3 R modulation becomes lower, whereas at very high concentrations of IP 3 , channel activity persists at supramicromolar Ca 2+ concentrations (11,12). This mechanism of dual-ligand regulat...

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“…In each case, the single-channel open probability (P o ) of IP 3 -activated channels displayed a bell-shaped dependence on cytosolic Ca 2þ concentration. Evidence that purified IP 3 R1 could be stimulated, but not inhibited, by cytosolic Ca 2þ (Thrower et al 1998;Michikawa et al 1999) raised the possibility that Ca 2þ inhibition might be mediated by an accessory protein, although it has yet to be identified. The same explanation perhaps accounts for some reports, often derived from bilayer recordings, in which Ca 2þ was suggested not to inhibit IP 3 R2 or IP 3 R3 (Horne and Meyer 1995;Hagar et al 1998;Miyakawa et al 1999;Ramos-Franco et al 2000).…”

Section: Regulation Of Ip 3 Receptors By Ca 2þ and Ipmentioning

confidence: 99%

“…Stimulation of IP 3 R by cytosolic Ca 2þ is universally observed even with purified IP 3 R reconstituted into lipid bilayers (Ferris et al 1989;Hirota et al 1995;Michikawa et al 1999), suggesting that this essential Ca 2þ -binding site probably resides within the primary sequence of the IP 3 R. At least seven cytosolic Ca 2þ -binding sites have been identified within IP 3 R1 (Sienaert et al 1996;Sienaert et al 1997), but the physiological relevance of these sites is unresolved. Two of the sites (residues 304-381 and 378-450) are within the IP 3 -binding core, for which there is a high-resolution structure (Bosanac et al 2002).…”

Section: Regulation Of Ip 3 Receptors By Ca 2þ and Ipmentioning

confidence: 99%

“…CaM is a ubiquitously expressed, EF-hand containing, Ca 2þ -binding protein that serves as the Ca 2þ -sensor for many cellular events (Gnegy 1993). All IP 3 R subtypes are inhibited by Ca 2þ -CaM Michikawa et al 1999;Missiaen et al 1999;Adkins et al 2000;Missiaen et al 2000), and CaM has been shown to restore Ca 2þ inhibition to purified IP 3 R Michikawa et al 1999;Nosyreva et al 2002). Yet, it has proven difficult to relate these functional effects of CaM to either its effects on IP 3 binding or to identified CaM-binding sites within IP 3 R. CaM inhibits IP 3 binding to IP 3 R1 in a Ca 2þ -independent manner (Patel et al 1997;Cardy and Taylor 1998), through a site that probably lies within the SD (Adkins et al 2000;Sienaert et al 2002).…”

Section: Regulation Of Ip 3 Receptors By Ca 2þ and Ipmentioning

confidence: 99%

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IP3 Receptors: Toward Understanding Their Activation

Taylor¹,

Tovey²

2010

Cold Spring Harbor Perspectives in Biology

258

190

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Inositol 1,4,5-trisphosphate receptors (IP 3 R) and their relatives, ryanodine receptors, are the channels that most often mediate Ca 2þ release from intracellular stores. Their regulation by Ca 2þ allows them also to propagate cytosolic Ca 2þ signals regeneratively. This brief review addresses the structural basis of IP 3 R activation by IP 3 and Ca 2þ . IP 3 initiates IP 3 R activation by promoting Ca 2þ binding to a stimulatory Ca 2þ -binding site, the identity of which is unresolved. We suggest that interactions of critical phosphate groups in IP 3 with opposite sides of the clam-like IP 3 -binding core cause it to close and propagate a conformational change toward the pore via the adjacent N-terminal suppressor domain. The pore, assembled from the last pair of transmembrane domains and the intervening pore loop from each of the four IP 3 R subunits, forms a structure in which a luminal selectivity filter and a gate at the cytosolic end of the pore control cation fluxes through the IP 3 R.

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Calmodulin Mediates Calcium-Dependent Inactivation of the Cerebellar Type 1 Inositol 1,4,5-Trisphosphate Receptor

Cited by 158 publications

References 60 publications

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Mechanistic basis of bell-shaped dependence of inositol 1,4,5-trisphosphate receptor gating on cytosolic calcium

IP3 Receptors: Toward Understanding Their Activation

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Calmodulin Mediates Calcium-Dependent Inactivation of the Cerebellar Type 1 Inositol 1,4,5-Trisphosphate Receptor

Cited by 158 publications

References 60 publications

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca 2+ release through IP 3 receptors

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca 2+ release through IP 3 receptors

Mechanistic basis of bell-shaped dependence of inositol 1,4,5-trisphosphate receptor gating on cytosolic calcium

IP3 Receptors: Toward Understanding Their Activation

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Product

Resources

About

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors