Michael Fill
PERSPECTIVE
Over the last decade, the roles of the RyR and IP3R Ca2+ release channels in intracellular Ca2+
signaling has started to be defined. Many basic properties of the different RyR and IP3R Ca2+ release
channels have been described. Further, small local elementary Ca2+ release events that are generated by
these channels were identified and the hierarchical nature of Ca2+ signaling revealed. The Ca2+ mobilized
by individual channels generates local elemental Ca2+
release events. These local Ca2+ release events
combine to produce the global Ca2+ release signals
that drive a host of cellular phenomena. The specific sub-cellular localization of particular types of intracellular Ca2+ release channels is an important
factor in the complex spatiotemporal nature of intracellular Ca2+ signaling. Although certain key
elements and general concepts that govern intracellular Ca2+ release are known, it is clear that
there are several others that are either poorly understood or entirely unknown.
Over the next decade, I believe it will become increasingly apparent that individual intracellular Ca2+ release channels are just one
component in complex multi-protein Ca2+ signaling
assemblies. I also believe that these assemblies will have all the components (i.e. surface receptors, enzymes, regulatory proteins, release channels, structural elements, etc.) that allow them to carry out specific and local Ca2+ signaling tasks. Research
emphasis will gradually shift away from defining the function of the individual Ca2+ signaling elements to
defining how a collection of elements operate in concert to control a local signaling process. In this context, defining mechanism will likely become increasingly important and challenging.
References
1. Adams B.A., Tanabe T., Mikami A., Numa S., Beam KG. 1990. Intramembrane charge movement restored in dysgenic skeletal muscle by injection of dihydropyridine receptor cDNAs. Nature. 346(6284):569-72.
2. Armisen R., Sierralta J., Vélez P., Naranjo D., Suarez- Isla B.A. 1996. Modal gating in neuronal and skeletal muscle ryanodine-sensitive Ca2+ release channels.
Am.J.Physiol. 271(1 Pt 1):C144-53.
3. Armstrong C.M., Bezanilla F.M., Horowicz P. 1972. Twitches in the presence of ethylene glycol bis(- aminoethyl ether)-N,N'-tetracetic acid. Biochimica et Biophysica Acta. 267(3):605-8.
4. Berridge M.J. 1987. Inositol Trisphosphate and Diacylglycerol:Two Interacting second messengers, Ann. Review Biochem. 56:159-193.
5. Berridge M.J. and R.F Irvine. 1984. Inositol Trisphosphate: A Novel Second Messenger in Cellular Signal Transduction, Nature 312:315-321.
6. Berridge, M.J., 1993. Inositol Trisphosphate and Calcium Signaling, Nature 361:567-570.
7. Bers, D.M. Excitation-contraction coupling and cardiac contractile force. Kluwer Academic Pub (London), 1990. Figure 4: The Ca2+ sensitivity of single type-1 IP
3R channels
in planar lipid bilayers are represented as solid lines. These plots are based on the work of Bezprozvanny et al. (1991). Dotted line represents the theoretical free Ca2+ changes that
8. Bers D.M., Fill M. 1998. Coordinated feet and the dance of ryanodine receptors. Science. 281:790-791. 9. Bezprozvanny I. et al. 1991. Bell-shaped Calcium-
response Curves of Ins(1,4,5)P3- and Calcium-gated
Channels from Endoplasmic Reticulum of Cerebellum, Nature 351:751-754.
10. Bridge JH, Ershler PR, Cannell MB. 1999. Properties of Ca2+ sparks evoked by action potentials in mouse
ventricular myocytes. J Physiol 518:469-478.
11. Cheng H., Lederer w.j., Cannell m.b. 1993. Calcium sparks: Elementary events underlying exitation- contraction coupuling in heart muscle. Science 262:740-8.
12. Chu A., Fill M., Stefani E., Entman M.L. 1993. Cytoplasmic Ca2+ does not inhibit the cardiac muscle
sarcoplasmic reticulum ryanodine receptor Ca2+
channel, although Ca2+-induced Ca2+ inactivation of
Ca2+ release is observed in native vesicles.
J.Memb.Biol. 135(1):49-59.
13. Copello J.A., Barg S., Onoue H., Fleischer S. 1997. Heterogeneity of Ca gating of skeletal muscle and cardiac ryanodine receptors. Biophys.J. 73(1):141-56. 14. Coronado R., Morrissette J., Sukhareva M., Vaughan
D.M. 1994. Structure and function of ryanodine receptors. Am.J.Physiol. 266 (Cell Physiol. 35):C1485- C1504.
15. Dettbarn C, Gyorke S, Palade P. 1994. Many agonists induce "quantal" Ca2+ release or adaptive behavior in muscle ryanodine receptors. Mol Pharmacol. 46:502- 507.
16. Ehrlich B.E. et al. 1994. The Pharmacology of Intracellular Ca2+-release Channels, TiPS 15:145-149.
17. Ellies-Davies G.C.R., Kaplan j.h., Barsotti R.J. 1996. Laser photolysis of caged calcium: rates of calcium release by nitrophenyl-EGTA and DM-nitrophen. Biophys.J. 70:1006-1016.
18. Escobar A.L., Cifuentes F., Vergara J.L. 1995. Detection of Ca2+-transients elicited by flash photolysis of DM-
nitrophen with a fast calcium indicator. FEBS Letter 364:335-338.
19. Fabiato A. 1985. Time and calcium dependence of activation and inactivation of calcium-induced release of calcium from the sarcoplacmic reticulum of a skinned cardiac Purkinje cell. J.Gen.Physiol. 85:247-289. 20. Franzini-Armstrong C., Kenney l.J., Varriano-Marson E.
1987. The structure of calsequestrin in triads of vertabrate skeletal muscle: a deep-etch study. J. Cell Biol. 105:49-56.
21. Furuichi T., Furutama D., Hakamata Y., Nakai J., Takeshima H., Mikoshiba K. 1994. Multiple types of ryanodine receptor/Ca2+ release channels are differentially expressed in rabbit brain. Journal of Neuroscience. 14(8):4794-805.
22. Györke S., Fill m. 1993. Ryanodine receptor adaptation: control mechanism of Ca2+-induced Ca2+
release in heart. Science 1993; 260:807-809.
23. Györke S., Vélez P., Suárez-Isla B.A., Fill M. 1994. Activation of single cardiac and skeletal ryanodine receptor channels by flash photolysis of caged Ca2+ .
Biophys. J. 66:1879-1886.
24. Györke I., Györke S. 1996. Adaptive control of intracellular Ca2+ release in C2C12 mouse myotubes.
Pflügers Arch. 431(6):838-843.
25. Hain J., Onoue h., Mayrleitner m., Fleischer s., Schindler h. 1995. Phosphorylation modulates the function of the calciom release channel of sarcoplasmic reticulum from cardiac muscle. J.Biol.Chem. 270:2074- 2081.
26. Imredy JP, Yue DT. 1994. Mechanism of Ca(2+)- sensitive inactivation of L-type Ca2+ channels. Neuron. 12:1301-1318.
27. Kaftan, E.J, B.E. Ehrlich and J. Watras. 1997. Inositol 1,4, 5-trisphosphate (InsP3) and calcium interact to
increase the dynamic range of InsP3 receptor-
dependent calcium signaling. J.Gen.Physiol. 110:529- 538.
28. Kim K.C., Caswell A.H., Talvenheimo J.A., Brandt N.R. 1990. Isolation of a terminal cisterna protein which may link the dihydropyridine receptor to the junctional foot protein in skeletal muscle. Biochemistry. 29(39):9281-9.
29. Lamb G.D., Stephenson D.G. 1994. Activation of ryanodine receptors by flash photolysis of caged Ca2+.
Biophys. J. 68:946-948.
30. Langer GA, Peskoff A. 1996. Calcium concentration and movement in the diadic cleft space of the cardiac ventricular cell. Biophys.J. 70:1169-1182.
31. Laver D.R., Roden l.d., Ahern g.p., Eager k.r., Junankar p.a., Dulhunty a.f. 1995. Cytoplasmic Ca2+ inhibits the
ryanodine receptor from cardiac muscle. J. Memb. Biol. 147:7-22.
32. Laver D.R., Curtis B.A. 1996. Response of ryanodine receptor channels to Ca2+ steps produced by rapid
solution exchange. Biophys. J. 71:732-741
33. Laver D.R, Lamb G.D. 1998. Inactivation of Ca2+
release channels (ryanodine receptors RyR1 and RyR2) with rapid steps in [Ca2+] and voltage. Biophys J. 74:2352-2364.
34. Lipp P., Laine M., Tovey S.C., Burrell K.M., Berridge M.J., Li W. and Bootman MD. 2000. Functional InsP3 receptors that may modulate excitation-contraction coupling in the heart. Curr. Biol. 2000 Jul 27-Aug 10;10(15):939-42
35. Lukyanenko V, Wiesner TF, Györke S. 1998. Termination of Ca2+ release during Ca2+ sparks in rat
ventricular myocytes. J.Physiol. 507:667-677.
36. Lukyanenko V, Györke S. 1999. Ca2+ sparks and Ca2+
waves in saponin-permeabilized rat ventricular myocytes. J.Physiol. 521:575-585.
37. Lukyanenko V, Gyorke I, Subramanian S, Smirnov A, Wiesner TF, Gyorke S. 2000. Inhibition of Ca2+ Sparks
by Ruthenium Red in Permeabilized Rat Ventricular Myocytes. Biophys. J. 79(3).
38. Mak, D.-O. D., S. McBride and J.K. Foskett. 1998. Inositol-1,4,5-trisphosphate activation of inositol trisphosphate receptor Ca2+ channel by ligand tuning of
Ca2+ inhibition. Proc. Natl. Acad. Sci. USA 95:15821-
15825.
39. Marks A.R., Tempst p., Hwang k.s., Taubman m.b., Inui c., Chadwick c.c., Fleischer s., Nadal-Ginard b. 1989. Molecular cloning and characterization of the ryanodine receptor/junctional channel complex cDNA from skeletal muscle sarcoplasmic reticulum. Proc. Natl. Acad. Sci. USA 86:8683-8687.
40. Marks AR. 1996. Cellular functions of immunophilins. Physiological Reviews. 76(3):631-49.
41. Marx O.S., Ondrias K., Marks A.R. 1998 Coupled gating between individual skeletal muscle calcium release channels. Science. 281:818-820.
42. McCall E, Li L, Satoh H, Shannon TR, Blatter LA, Bers DM. 1996. Effects of FK-506 on contraction and Ca2+
transients in rat cardiac myocytes. Circ. Res. Dec;79(6):1110-21
43. Mejia-Alvarez R, Kettlun C, Rios E, Stern M, Fill M. 1999. Unitary Ca2+ current through cardiac ryanodine
receptor channels under quasi-physiological ionic conditions. J Gen Physiol. 113:177-186.
44. Mignery G.A., Sudhof T.C., Takei K., Camilli P. 1989. Putative receptor for inositol 1,4,5-trisphosphate similar to ryanodine receptor. Nature. 342(6246):192-5. 45. Mignery G.A. and T.C. Sudhof. 1993. Molecular
Analysis of Inositol 1,4,5-Trisphosphate Receptors, Methods Neurosci.18: 247-265.
46. Moschella, M.C. and A.R Marks. 1993. Inositol 1,4,5- Trisphosphate Receptor Expression in Cardiac Myocytes, J. Cell Biol. 120:1137-1146.
47. Näbauer M., Morad m. 1990. Ca2+-induced Ca2+ release
as examined by photolysis of caged Ca2+ in single
ventricular myocytes. Am. J. Physiol. 285:C189-93. 48. Parker I., Zang w.j., Wier w.g. 1996. Ca2+ sparks
involving multiple Ca2+ release sites along Z-lines in
49. Pizarro G., Shirokova N., Tsugorka A., Rios E. 1997. 'Quantal' calcium release operated by membrane voltage in frog skeletal muscle. J.Physiol. 501:289-303. 50. Ramos-Franco J. et al. 1998. Isoform-specific Function
of Single Inositol 1,4,5-Trisphosphate Receptor Channels, Biophys. J. 75:834-839.
51. Rousseau E., Meissner G. 1989. Single cardiac sarcoplasmic reticulum Ca-release channel: activation by caffeine. Am. J. Physiol.. 256(2 Pt 2):H328-33. 52. Schiefer A., Meissner G., Isenberg G. 1995. Ca2+
activation and Ca2+ inactivation of canine reconstituted
cardiac sarcoplasmic reticulum Ca(2+)-release channels.
J. Physiol. 489:337-348.
53. Schneider M.F., Chandler W.K. 1976. Effects of membrane potential on the capacitance of skeletal muscle fibers. Journal of General Physiology. 67(2):125-63.
54. SHAM J.S., Song L.S, Chen Y., Deng L.H. Stern M.D., Lakatta E.G., Cheng H. 1998. Termination of Ca2+
release by a local inactivation of ryanodine receptors in cardiac myocytes. Proc.Natl.Acad.Sci.USA. 95:15096- 15101.
55. Sitsapesan R., Williams a.j. 1995. The gating of the sheep skeletal sarcoplacmic reticulum Ca2+ release
channel is regulated by luminal Ca2+. J. Memb.. Biol.
146:133-144.
56. Stern M.D. 1992. Theory of excitation-contraction coupling in cardiac muscle. Biophys J; 63(2):497-517. 57. Stern M.D., Song L.S., Cheng H, Sham J.S., Yang H.T.,
Boheler K.R., Rios E. 1999. Local control models of cardiac excitation-contraction coupling. A possible role for allosteric interactions between ryanodine receptors. J.Gen.Physiol. 113:469-489.
58. Takeshima H. 1993. Primary structure and expression from cDNAs of the ryanodine receptor. Ann. NY Acad. Sci. USA 707:165-177.
59. Thrower EC, Hagar RE, Ehrlich BE. 2001. Regulation of Ins(1,4,5)P3 receptor isoforms by endogenous modulators. Trends Pharmacol Sci, 22(11):580-6 60. Tripathy A., Meissner G. 1996. Sarcoplasmic reticulum
lumenal Ca2+ has access to cytosolic activation and
inactivation sites of skeletal muscle Ca2+ release
channel. Biophys J 70:2600-2615.
61. Valdivia H.H., Kaplan J.H, Ellies-Davies G.C.R. and Lederer W.J. 1995. Rapid adaptation of cardiac
ryanodine receptors: modulation by Mg+ and
phosphorylation. Science. 267:1997-2000.
62. Velez P., Gyorke S., Escobar A., Vergara J., Fill M. 1997. Adaptation of single cardiac ryanodine receptor channels. Biophys. J. 72:691-697.
63. Zahradníková A., Zahradník I. 1995. Description of modal gating of the cardiac calcium release channel in planar lipid membranes. Biophys. J. 69:1780-1788. 64. Villalba-Galea CA, Suarez-Isla BA, Fill M, Escobar AL.
1998. Kinetic model for ryanodine receptor adaptation. Biophys J 74:A58.
65. Watras J. et al. 1991. Inositol 1,4,5-Trisphosphate- gated Channels in Cerebellum: Presence of Multiple Conductance States, J. Neurosci. 11:3239-3245. 66. Yao Y., Choi J. and Parker I. 1995. Quantal puffs of
intracellular Ca2+ evoked by inositol trisphosphate in Xenopus oocytes. J Physiol 1995 Feb 1;482 ( Pt 3):533-53
Yasui K, Palade P, Gyorke S. 1994. Negative control mechanism with features of adaptation controls Ca2+ release in cardiac myocytes. Biophys J 67:457-460. 67. Zahradníková A, Zahradník I. 1996. A minimal gating
model for the cardiac calcium release channel. Biophys J 71:2996-3012.
68. Zahradníková A., Zahradník I., Györke I., Györke S. 1999. Rapid activation of the cardiac ryanodine receptor by submillisecond calcium stimuli. J Gen Physiol. 114:787-798.
69. Zorzato F., Fljii J., Otsu K., Phillips M., Green N.M., Lai F.A., Meissner G., Maclennan D.H. 1990. Molecular cloning of cDNA encoding human and rabbit forms of the Ca2+ release channel (ryanodine receptor) of skeletal muscle sarcoplasmic reticulum. Journal of Biological Chemistry. 265(4):2244-56.
70. Zucker R.S. 1993. Calcium concentration clamp: spike and reversible pulses using the photolabile chelator DM-nitrophen. Cell Calcium. 14: 87-100.
Correspondence: Michael Fill
Loyola University Chicago Department of Physiology 2160 South First Avenue Maywood, IL 60153