Chlorocresol: an activator of ryanodine receptor-mediated Ca2+ release

F Zorzato, E Scutari, V Tegazzin, E Clementi and S Treves

Institute of General Pathology, University of Ferrara, Italy.

In the present study we investigated the effect of the compound chlorocresol on intracellular Ca2+ homeostasis. Three different systems that have been shown to express the ryanodine receptor Ca2+ channel were chosen, i.e., skeletal muscle sarcoplasmic reticulum, cerebellar microsomes, and PC12 cells. In skeletal muscle sarcoplasmic reticulum, 4-chloro-m-cresol was found to be a potent activator of Ca2+ release mediated by a ruthenium red/caffeine-sensitive Ca2+ release channel. In cerebellar microsomes, this compound released Ca2+ from an inositol- 1,4,5-trisphosphate-insensitive store, suggesting that there too it was acting at the ryanodine receptor level. When tested on PC12 cells, chlorocresol released Ca2+ from a caffeine- and thapsigargin-sensitive intracellular store. In addition, the compound was capable of releasing Ca2+ after pretreatment of PC12 cells with bradykinin, suggesting that it acts on a channel contained within an intracellular Ca2+ store that is distinct from that sensitive to inositol-1,4,5-trisphosphate. Structure-activity relationship analyses suggest that the chloro and methyl groups in chlorocresols are important for the activation of the ryanodine receptor Ca2+ release channel.

Volume 44, Issue 6, pp. 1192-1201, 12/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				T. Tazzeo, Y. Zhang, S. Keshavjee, and L. J. Janssen Ryanodine receptors decant internal Ca2+ store in human and bovine airway smooth muscle Eur. Respir. J., August 1, 2008; 32(2): 275 - 284. [Abstract] [Full Text] [PDF]

				R. Jimenez-Moreno, Z.-M. Wang, R. C. Gerring, and O. Delbono Sarcoplasmic Reticulum Ca2+ Release Declines in Muscle Fibers from Aging Mice Biophys. J., April 15, 2008; 94(8): 3178 - 3188. [Abstract] [Full Text] [PDF]

				A. V. Zhdanov, M. W. Ward, J. H. M. Prehn, and D. B. Papkovsky Dynamics of Intracellular Oxygen in PC12 Cells upon Stimulation of Neurotransmission J. Biol. Chem., February 29, 2008; 283(9): 5650 - 5661. [Abstract] [Full Text] [PDF]

				P. Aracena-Parks, S. A. Goonasekera, C. P. Gilman, R. T. Dirksen, C. Hidalgo, and S. L. Hamilton Identification of Cysteines Involved in S-Nitrosylation, S-Glutathionylation, and Oxidation to Disulfides in Ryanodine Receptor Type 1 J. Biol. Chem., December 29, 2006; 281(52): 40354 - 40368. [Abstract] [Full Text] [PDF]

				B. A. Kachoei, R. J. Knox, D. Uthuza, S. Levy, L. K. Kaczmarek, and N. S. Magoski A Store-Operated Ca2+ Influx Pathway in the Bag Cell Neurons of Aplysia J Neurophysiol, November 1, 2006; 96(5): 2688 - 2698. [Abstract] [Full Text] [PDF]

				B. Allard, H. Couchoux, S. Pouvreau, and V. Jacquemond Sarcoplasmic reticulum Ca2+ release and depletion fail to affect sarcolemmal ion channel activity in mouse skeletal muscle J. Physiol., August 15, 2006; 575(1): 69 - 81. [Abstract] [Full Text] [PDF]

				J. D. Fessenden, W. Feng, I. N. Pessah, and P. D. Allen Amino Acid Residues Gln4020 and Lys4021 of the Ryanodine Receptor Type 1 Are Required for Activation by 4-Chloro-m-cresol J. Biol. Chem., July 28, 2006; 281(30): 21022 - 21031. [Abstract] [Full Text] [PDF]

				A. R. Jacobson, S. T. Moe, P. D. Allen, and J. D. Fessenden Structural Determinants of 4-Chloro-m-cresol Required for Activation of Ryanodine Receptor Type 1 Mol. Pharmacol., July 1, 2006; 70(1): 259 - 266. [Abstract] [Full Text] [PDF]

				A. Verkhratsky Physiology and Pathophysiology of the Calcium Store in the Endoplasmic Reticulum of Neurons Physiol Rev, January 1, 2005; 85(1): 201 - 279. [Abstract] [Full Text] [PDF]

				L. G. Weigl, C. Ludwig-Papst, and H. G. Kress 4-Chloro-m-Cresol Cannot Detect Malignant Hyperthermia Equivocal Cells in an Alternative Minimally Invasive Diagnostic Test of Malignant Hyperthermia Susceptibility Anesth. Analg., July 1, 2004; 99(1): 103 - 107. [Abstract] [Full Text] [PDF]

				E. Esteve, S. Smida-Rezgui, S. Sarkozi, C. Szegedi, I. Regaya, L. Chen, X. Altafaj, H. Rochat, P. Allen, I. N. Pessah, et al. Critical Amino Acid Residues Determine the Binding Affinity and the Ca2+ Release Efficacy of Maurocalcine in Skeletal Muscle Cells J. Biol. Chem., September 26, 2003; 278(39): 37822 - 37831. [Abstract] [Full Text] [PDF]

				J. D. Fessenden, C. F. Perez, S. Goth, I. N. Pessah, and P. D. Allen Identification of a Key Determinant of Ryanodine Receptor Type 1 Required for Activation by 4-Chloro-m-cresol J. Biol. Chem., August 1, 2003; 278(31): 28727 - 28735. [Abstract] [Full Text] [PDF]

				C. H. George, G. V. Higgs, J. J. Mackrill, and F. A. Lai Dysregulated Ryanodine Receptors Mediate Cellular Toxicity: RESTORATION OF NORMAL PHENOTYPE BY FKBP12.6 J. Biol. Chem., August 1, 2003; 278(31): 28856 - 28864. [Abstract] [Full Text] [PDF]

				T. Yang, T. A. Ta, I. N. Pessah, and P. D. Allen Functional Defects in Six Ryanodine Receptor Isoform-1 (RyR1) Mutations Associated with Malignant Hyperthermia and Their Impact on Skeletal Excitation-Contraction Coupling J. Biol. Chem., July 3, 2003; 278(28): 25722 - 25730. [Abstract] [Full Text] [PDF]

				F. Aguado, J. F. Espinosa-Parrilla, M. A. Carmona, and E. Soriano Neuronal Activity Regulates Correlated Network Properties of Spontaneous Calcium Transients in Astrocytes In Situ J. Neurosci., November 1, 2002; 22(21): 9430 - 9444. [Abstract] [Full Text] [PDF]

				A. Varadi and G. A. Rutter Dynamic Imaging of Endoplasmic Reticulum Ca2+ Concentration in Insulin-Secreting MIN6 Cells Using Recombinant Targeted Cameleons: Roles of Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA)-2 and Ryanodine Receptors Diabetes, February 1, 2002; 51(90001): S190 - 201. [Abstract] [Full Text] [PDF]

				T. Girard, D. Cavagna, E. Padovan, G. Spagnoli, A. Urwyler, F. Zorzato, and S. Treves B-lymphocytes from Malignant Hyperthermia-susceptible Patients Have an Increased Sensitivity to Skeletal Muscle Ryanodine Receptor Activators J. Biol. Chem., December 14, 2001; 276(51): 48077 - 48082. [Abstract] [Full Text] [PDF]

				N. Tilgen, F. Zorzato, B. Halliger-Keller, F. Muntoni, C. Sewry, L. M. Palmucci, C. Schneider, E. Hauser, F. Lehmann-Horn, C. R. Muller, et al. Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis Hum. Mol. Genet., December 1, 2001; 10(25): 2879 - 2887. [Abstract] [Full Text] [PDF]

				E. Hosoi, C. Nishizaki, K. L. Gallagher, H. W. Wyre, Y. Matsuo, and Y. Sei Expression of the Ryanodine Receptor Isoforms in Immune Cells J. Immunol., November 1, 2001; 167(9): 4887 - 4894. [Abstract] [Full Text] [PDF]

				S. Choisy, C. Huchet-Cadiou, and C. Léoty Differential Effects of 4-Chloro-m-cresol and Caffeine on Skinned Fibers from Rat Fast and Slow Skeletal Muscles J. Pharmacol. Exp. Ther., September 1, 2000; 294(3): 884 - 893. [Abstract] [Full Text]

				C. P. Baur, L. Bellon, P. Felleiter, M. Fiege, R. Fricker, K. Glahn, J. J. A. Heffron, A. Herrmann-Frank, K. Jurkat-Rott, W. Klingler, et al. A Multicenter Study of 4-Chloro-m-cresol for Diagnosing Malignant Hyperthermia Susceptibility Anesth. Analg., January 1, 2000; 90(1): 200 - 200. [Abstract] [Full Text] [PDF]

				D. Krizaj, J.-X. Bao, Y. Schmitz, P. Witkovsky, and D. R. Copenhagen Caffeine-Sensitive Calcium Stores Regulate Synaptic Transmission from Retinal Rod Photoreceptors J. Neurosci., September 1, 1999; 19(17): 7249 - 7261. [Abstract] [Full Text] [PDF]

				S. Choisy, C. Huchet-Cadiou, and C. Léoty Sarcoplasmic Reticulum Ca2+ Release by 4-Chloro-m-Cresol (4-CmC) in Intact and Chemically Skinned Ferret Cardiac Ventricular Fibers J. Pharmacol. Exp. Ther., August 1, 1999; 290(2): 578 - 586. [Abstract] [Full Text]

				Y. Sei, K. L. Gallagher, and A. S. Basile Skeletal Muscle Type Ryanodine Receptor Is Involved in Calcium Signaling in Human B Lymphocytes J. Biol. Chem., February 26, 1999; 274(9): 5995 - 6002. [Abstract] [Full Text] [PDF]

				G. G. Du and D. H. MacLennan Functional Consequences of Mutations of Conserved, Polar Amino Acids in Transmembrane Sequences of the Ca2+ Release Channel (Ryanodine Receptor) of Rabbit Skeletal Muscle Sarcoplasmic Reticulum J. Biol. Chem., November 27, 1998; 273(48): 31867 - 31872. [Abstract] [Full Text] [PDF]

				C. W. Ward, E. E. Spangenburg, L. M. Diss, and J. H. Williams Effects of varied fatigue protocols on sarcoplasmic reticulum calcium uptake and release rates Am J Physiol Regulatory Integrative Comp Physiol, July 1, 1998; 275(1): R99 - R104. [Abstract] [Full Text] [PDF]

				M. S. Islam, I. Leibiger, B. Leibiger, D. Rossi, V. Sorrentino, T. J. Ekstrom, H. Westerblad, F. H. Andrade, and P.-O. Berggren In situ activation of the type 2 ryanodine receptor in pancreatic beta cells requires cAMP-dependent phosphorylation PNAS, May 26, 1998; 95(11): 6145 - 6150. [Abstract] [Full Text] [PDF]

				D. H. DiJulio, E. L. Watson, I. N. Pessah, K. L. Jacobson, S. M. Ott, E. D. Buck, and J. C. Singh Ryanodine Receptor Type III (Ry3R) Identification In Mouse Parotid Acini. PROPERTIES AND MODULATION OF [3H]RYANODINE-BINDING SITES J. Biol. Chem., June 20, 1997; 272(25): 15687 - 15696. [Abstract] [Full Text] [PDF]

				R. Zucchi and S. Ronca-Testoni The Sarcoplasmic Reticulum Ca2+ Channel/Ryanodine Receptor: Modulation by Endogenous Effectors, Drugs and Disease States Pharmacol. Rev., March 1, 1997; 49(1): 1 - 52. [Abstract] [Full Text] [PDF]

				J. I. E. Bruce, T. J. Shuttleworth, D. R. Giovannucci, and D. I. Yule Phosphorylation of Inositol 1,4,5-Trisphosphate Receptors in Parotid Acinar Cells. A MECHANISM FOR THE SYNERGISTIC EFFECTS OF cAMP ON Ca2+ SIGNALING J. Biol. Chem., January 4, 2002; 277(2): 1340 - 1348. [Abstract] [Full Text] [PDF]

				K. J. Mitchell, P. Pinton, A. Varadi, C. Tacchetti, E. K. Ainscow, T. Pozzan, R. Rizzuto, and G. A. Rutter Dense core secretory vesicles revealed as a dynamic Ca2+ store in neuroendocrine cells with a vesicle-associated membrane protein aequorin chimaera J. Cell Biol., October 1, 2001; 155(1): 41 - 52. [Abstract] [Full Text] [PDF]