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Ryanodine Receptors, Voltage-Gated Calcium Channels and Their Relationship with Protein Kinase a in the Myocardium

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Ryanodine Receptors, Voltage-Gated Calcium Channels and Their Relationship with Protein Kinase a in the Myocardium Physiol. Res. 57: 141-149, 2008 MINIREVIEW Ryanodine Receptors, Voltage-Gated Calcium Channels and Their Relationship with Protein Kinase A in the Myocardium M. M. PETROVIČ1,2, K. VALEŠ2, B. PUTNIKOVIČ3, V. DJULEJIČ4, D. M. MITROVIČ1 1Institute of Medical Physiology, School of Medicine, Belgrade, Serbia, 2Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic, 3Cardiology Department, Clinical hospital Center Zemun, School of Medicine, Belgrade and 4Institute of Anatomy, School of Medicine, Belgrade, Serbia Received December 1, 2006 Accepted March 15, 2007 On-line available April 25, 2007 Summary However, their defects and alterations can result in serious We present a review about the relationship between ryanodine disturbances. receptors and voltage-gated calcium channels in myocardium, and also how both of them are related to protein kinase A. Key words Ryanodine receptors, which have three subtypes (RyR1-3), are Ryanodine receptors • Calcium channels • Protein kinase A • located on the membrane of sarcoplasmic reticulum. Different Heart failure subtypes of voltage-gated calcium channels interact with ryanodine receptors in skeletal and cardiac muscle tissue. The Corresponding author mechanism of excitation-contraction coupling is therefore M. M. Petrovic, Institute of Physiology, Academy of Sciences of different in the skeletal and cardiac muscle. However, in both the Czech Republic, Vídeňská 1083, 14220 Prague 4, Czech tissues ryanodine receptors and voltage-gated calcium channels Republic. E-mail: [email protected] seem to be physically connected. FK-506 binding proteins (FKBPs) are bound to ryanodine receptors, thus allowing their concerted activity, called coupled gating. The activity of both Introduction ryanodine receptors and voltage-gated calcium channels is positively regulated by protein kinase A. These effects are, In general, Ca2+ ions can flow into the cell from therefore, components of the mechanism of sympathetic the outside, through different types of channels, or they stimulation of myocytes. The specificity of this enzyme’s targeting can be released from internal stores. This local increase in is achieved by using different A kinase adapting proteins. cytosolic [Ca2+] that creates a microdomain is used by Different diseases are related to inborn or acquired changes in various systems to start distinct events in the cell. (Fill ryanodine receptor activity in cardiac myocytes. Mutations in the and Copello 2002). Ryanodine receptors (RyRs) are a cardiac ryanodine receptor gene can cause catecholamine- particular type of channels located on the membranes of provoked ventricular tachycardia. Changes in phosphorylation sarcoplasmic reticulum. They are widely expressed and state of ryanodine receptors can provide a credible explanation their distribution in the CNS is of particular importance for the development of heart failure. The restoration of their (Verkhratsky 2005), but here we will describe their role normal level of phosphorylation could explain the positive effect in the myocardium only. RyRs have a critical role in of beta-blockers in the treatment of this disease. In conclusion, excitation-contraction coupling in striated muscles (both molecular interactions of ryanodine receptors and voltage-gated skeletal and cardiac). They are inextricably related to calcium channels with PKA have a significant physiological role. voltage-gated calcium channels (VGCC). Recently, PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online) © 2008 Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres 142 Petrovic et al. Vol. 57 several different concepts emerged that try to relate Table 1. The nomenclature(s) used for describing the voltage- gated calcium channels. The currently used system, the system changes of phosphorylation state of both voltage-gated according to the alpha subunit distribution and the calcium channels and RyRs to physiological and electrophysiological system. pathological events in the myocardial cells. We will primarily describe these recent advances in ryanodine IUPHAR alpha subunit Electrophysiological receptor research, their interaction with VGCCs and the nomenclature nomenclature nomenclature influence of protein kinase A upon them. CaV1.1 α1S L Ryanodine receptors – genes and expression CaV1.2 α1C L So far, three types of ryanodine receptors have CaV1.3 α1D L been isolated, RyR1-RyR3 (Zorzato et al. 1990, CaV1.4 α1F L Hakamata et al. 1992). They are coded by three different CaV2.1 α1A P/Q genes, giving rise to enormous polypeptides (4872-5037 CaV2.2 α1B N amino acids). The distribution of RyRs in the organism is CaV2.3 α1E R generally tissue-specific: RyR1 predominates in skeletal CaV3.1 α1G T muscles, RyR2 in the cardiac muscle, whereas RyR3 has CaV3.2 α1H T a wide and, at a first glance, irregular distribution. CaV3.3 α1I T Structure of ryanodine receptors Structurally, there are larger receptors and larger for this same type of channels – dihydropyridine proteins than RyRs, but RyRs are the largest ion channels receptors (DHPR). According to this system, there are known to exist. Each molecule has more than 5000 amino other types of voltage-gated calcium channels, such as acids, with the molecular mass of ~600 kDa. Both ends of P/Q, R, N and T-type channels. A comparative list of the molecule (amino- and carboxy) are on the cytosolic these three systems is presented in Table 1. side of the membrane, i.e. on the outside from the sarcoplasmic reticulum lumen (Grunwald and Meissner Regulation of ryanodine receptor activity 1995), which implies an even number of transmembrane Ryanodine is a substance originally derived from segments. The protein itself is disproportionally divided the plant Ryania sp. Initially, it was used as an into cytosolic (~4000 aa) and transmembrane segment insecticide, but it was soon noticed that it is also toxic for (~1000 aa) (Rossi and Sorrentino 2002). humans and animals, because of its paralytic action on Since the complete receptor is a homotetramer, skeletal and cardiac muscles. However, at the beginning composed of subunits attached at their angles, its total it was not known why cardiac paralysis caused by mass is ~2.5 MDa (Serysheva et al. 2005). Due to such ryanodine was flaccid, whereas skeletal muscle paralysis an enormous size, RyRs are clearly visible under the was spastic. This difference is not trivial, because it electron microscope (the foot processes at the junction of indicates essential difference in the mechanism of sarcoplasmic reticulum and T-tubules). calcium handling in these two tissues: ryanodine blocks RyRs in the open state, thus practically emptying the Voltage-gated calcium channels sarcoplasmatic reticulum, because the calcium ions leak There are several existing nomenclature systems out. Contrary to cardiac muscle cells, the skeletal related to VGCC and this produces a lot of confusion. myocytes do not possess the strong membrane transport Throughout this paper, we shall use the most recent one systems for elimination of Ca2+ (Fill and Copello 2002), (Catterall 2000). The voltage-gated calcium channels in so that free cytosolic [Ca2+] increases, causing muscle the heart are usually designated as L-type calcium contraction. channels because after the activation their current is long- lasting. Due to their enormous importance in Function of ryanodine receptors in striated muscles cardiovascular pathology, large groups of blocking drugs As in other types of ion channels, we can have been developed. Structurally, these calcium blockers describe the selectivity, conductivity and activation can be divided into phenylalkylamines, dihydropyridines properties of RyR receptors. Compared to other ion and benzothiazepines. This explains another name used channels, their conductivity is enormous, the highest 2008 Ryanodine Receptors, Voltage-Gated Calcium Channels and PKA 143 Fig. 1. Interaction and positioning of RyRs and voltage- gated calcium channels in skeletal in cardiac muscle. A. In the skeletal muscle, there is an orderly association between RyR1 and CaV1.1: every other complete RyR1 channel is in contact with 4 CaV1.1 channels, each calcium channel interacting with a single RyR1 subunit. B. In cardiac muscle, there is a functional interaction of RyR2 with CaV1.2. However, their positioning is less regular, although physical interaction between them may exist (see text). C. Mutant animals without RyR1 genes are called dyspedic. The lack of RyR1 can not be compensated for by RyR2 to reestablish excitation- contraction coupling. D. Mutant animals without CaV1.1 are called dysgenic. SRM – sarcoplasmic reticulum membrane. known, in the order of nS, when the charge carriers are tissue are essential for cardiac, but not for skeletal monovalent cations. RyRs are moderately selective cation muscles (Armstrong et al. 1972, Dirksen and Beam channels (only 6 times more permeable to calcium than to 1999). Thus membrane potential change per se is not potassium). For comparison, CaV1.x channels are sufficient for cardiac contraction since calcium influx is 20 times more selective for calcium over potassium also required (Franzini-Armstrong and Protasi 1997). (Chen et al. 1997). Except for this anterograde interaction between RyRs should not be considered as isolated CaV1.1 and RyR1 (a synonym for excitation-contraction structures, because they are connected to a number
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