lanner_2012_ryanodine_receptor_physiology_and_its_role_in_disease.pdf

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Full Title: lanner_2012_ryanodine_receptor_physiology_and_its_role_in_disease.pdf
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Highlights

The ryanodine receptor (RyR) is the largest known ion channel; it is a homotetramer with a total mass of >2 MDa (each subunit is >550 kDa) (Page 2)
RyR is localized in the plasma membrane of ER/SR and is a large conductance channel capable of creating rapid transient increase in cytosolic Ca 2+ (Page 2)
creating rapid transient increase in cytosolic Ca 2+ [ 16, 17 ] . Four-ﬁ fths of the RyR protein is cytoplasmic and remaining, one-ﬁ fth, consists of luminal and membrane spanning domains. (Page 2)
Three mammalian isoforms of RyR have been isolated and the terminology, RyR1-3, is based on in which order the isoforms were isolated and tissue of initial puriﬁ cation (Page 2)
RyR1 is predominantly expressed in skeletal muscle and in cerebellar Purkinje neurons (Page 2)
RyR2 is greatly expressed in cardiac muscle [ 12, 13 ] , and is considered to be the most abundant isoform in the brain (Page 2)
RyR3 was ﬁ rst identiﬁ ed in the brain and is mainly found in cortical and hippocam-pal regions involved in learning and memory [ 15, 19, 21 ] . RyR3 is also expressed in the diaphragm (Page 2)
RyR exist predominantly in the closed state, but it has been noted that they open randomly in the absence of any stimulus (Page 2)
RyRs are modulated directly and indirectly by DHPR and by various ions, small molecules and proteins (Page 2)
RyR1-3 have a similar sequence homology (~65%), but despite this the isoforms differ markedly in their response to modulators (Page 4)
each subtype show different Ca 2+ binding afﬁ nities with RyR1 > RyR2 > RyR3 (Page 4)
RyR1 activity shows a bell-shaped response curve; activated by low Ca 2+ concentrations (~1 m M) and inhibition by high Ca 2+ concentrations (~1 mM) (Page 4)
The action potential in the t-tubules activates voltage sensitive dihydropyridine receptors (DHPRs), also known as L-type Ca 2+ channels (Ca v1.1 ), located in the t-tubular wall (Page 4)
The low myoplasmic Ca 2+ is maintained mainly by the adenosine trispho-sphate (ATP) consuming SR Ca 2+ -ATPase (SERCA) (Page 4)
Several mutations in both RyR1 and RyR2 are associated with human disorders. For example, the ﬁ rst of these to be identiﬁ ed in 1960 was malignant hyperthermia (MH) [ 37 ] and later central core disease (CCD), catecholaminergic polymorphic ventricular tachycardia (CPVT), and arrhyth-mogenic right ventricular dysplasia (ARVD) (Page 6)
in the heart increased phosphorylation is associated with increased SR Ca 2+ leak, which contrib-utes to reduced contractile function and increased propensity for arrhythmias (Page 6)
In skeletal muscle, increased SR Ca 2+ leak is linked to impaired muscle functions and exercise tolerance in mice (Page 6)
RyR1 is considered to be the major molecular target for dantrolene (Page 8)
adverse side-effects of dantrolene e.g. drowsiness, hepatoxicity, and signiﬁ cant muscle weakness preclude it from prophylactic usage (Page 8)
Many patients with CCD also test positive for MH susceptibility in the characteristic in vitro caffeine contracture test (IVCT). (Page 8)
CPVT was ﬁ rst described in the 1970s as a familial tachyarrhythmia disorder induced by exercise and emotional stress leading to sudden death in individuals with structurally normal hearts (Page 9)
CPVT is a rare but severe form of cardiac arrhyth-mia caused by mutations in RyR2 and CSQ2 (Page 9)
CSQ2 is a low-afﬁ nity, high-capacity Ca 2+ binding protein. CSQ2 is considered to be present in the SR as a mixture of monomers, dimers, and multimers. CSQ2 monomers interact with the RyR2 multicomplex via triadin and junctin (Page 9)
As it is recognized that b -adrenergic stimulation triggers ventricular tachycardia in CPVT, b -blockers are the considered ﬁ rst-line therapy today, but unfortunately they are not completely effective in preventing life-threatening arrhythmias (Page 9)
Recent reports show that ﬂ ecainide treatment completely prevents adrenergic-induced arrhythmias in a mouse model of CPVT and in humans with CSQ2 and RyR2 mutations (Page 10)
Lidocaine is another Na + blocker that does not inhibit RyR2 and has very low clinical effect on CPVT (Page 10)
ARVD is also a rare inherited disorder caused by RyR2 mutation located in same regions as CPVT and homologous with RyR1 mutations in MH and CCD (Page 10)
ARVD is characterized by substitution of the right ventricular myocardium with ﬁ brofatty tissue, which appears to be a result of progressive death of cardiomyo-cytes resulting from apoptosis and inﬂ ammation (Page 10)

lanner_2012_ryanodine_receptor_physiology_and_its_role_in_disease.pdf

Metadata

Author:
Full Title: lanner_2012_ryanodine_receptor_physiology_and_its_role_in_disease.pdf
Category: #books

Highlights

The ryanodine receptor (RyR) is the largest known ion channel; it is a homotetramer with a total mass of >2 MDa (each subunit is >550 kDa) (Page 2)
RyR is localized in the plasma membrane of ER/SR and is a large conductance channel capable of creating rapid transient increase in cytosolic Ca 2+ (Page 2)
creating rapid transient increase in cytosolic Ca 2+ [ 16, 17 ] . Four-ﬁ fths of the RyR protein is cytoplasmic and remaining, one-ﬁ fth, consists of luminal and membrane spanning domains. (Page 2)
Three mammalian isoforms of RyR have been isolated and the terminology, RyR1-3, is based on in which order the isoforms were isolated and tissue of initial puriﬁ cation (Page 2)
RyR1 is predominantly expressed in skeletal muscle and in cerebellar Purkinje neurons (Page 2)
RyR2 is greatly expressed in cardiac muscle [ 12, 13 ] , and is considered to be the most abundant isoform in the brain (Page 2)
RyR3 was ﬁ rst identiﬁ ed in the brain and is mainly found in cortical and hippocam-pal regions involved in learning and memory [ 15, 19, 21 ] . RyR3 is also expressed in the diaphragm (Page 2)
RyR exist predominantly in the closed state, but it has been noted that they open randomly in the absence of any stimulus (Page 2)
RyRs are modulated directly and indirectly by DHPR and by various ions, small molecules and proteins (Page 2)
RyR1-3 have a similar sequence homology (~65%), but despite this the isoforms differ markedly in their response to modulators (Page 4)
each subtype show different Ca 2+ binding afﬁ nities with RyR1 > RyR2 > RyR3 (Page 4)
RyR1 activity shows a bell-shaped response curve; activated by low Ca 2+ concentrations (~1 m M) and inhibition by high Ca 2+ concentrations (~1 mM) (Page 4)
The action potential in the t-tubules activates voltage sensitive dihydropyridine receptors (DHPRs), also known as L-type Ca 2+ channels (Ca v1.1 ), located in the t-tubular wall (Page 4)
The low myoplasmic Ca 2+ is maintained mainly by the adenosine trispho-sphate (ATP) consuming SR Ca 2+ -ATPase (SERCA) (Page 4)
Several mutations in both RyR1 and RyR2 are associated with human disorders. For example, the ﬁ rst of these to be identiﬁ ed in 1960 was malignant hyperthermia (MH) [ 37 ] and later central core disease (CCD), catecholaminergic polymorphic ventricular tachycardia (CPVT), and arrhyth-mogenic right ventricular dysplasia (ARVD) (Page 6)
in the heart increased phosphorylation is associated with increased SR Ca 2+ leak, which contrib-utes to reduced contractile function and increased propensity for arrhythmias (Page 6)
In skeletal muscle, increased SR Ca 2+ leak is linked to impaired muscle functions and exercise tolerance in mice (Page 6)
RyR1 is considered to be the major molecular target for dantrolene (Page 8)
adverse side-effects of dantrolene e.g. drowsiness, hepatoxicity, and signiﬁ cant muscle weakness preclude it from prophylactic usage (Page 8)
Many patients with CCD also test positive for MH susceptibility in the characteristic in vitro caffeine contracture test (IVCT). (Page 8)
CPVT was ﬁ rst described in the 1970s as a familial tachyarrhythmia disorder induced by exercise and emotional stress leading to sudden death in individuals with structurally normal hearts (Page 9)
CPVT is a rare but severe form of cardiac arrhyth-mia caused by mutations in RyR2 and CSQ2 (Page 9)
CSQ2 is a low-afﬁ nity, high-capacity Ca 2+ binding protein. CSQ2 is considered to be present in the SR as a mixture of monomers, dimers, and multimers. CSQ2 monomers interact with the RyR2 multicomplex via triadin and junctin (Page 9)
As it is recognized that b -adrenergic stimulation triggers ventricular tachycardia in CPVT, b -blockers are the considered ﬁ rst-line therapy today, but unfortunately they are not completely effective in preventing life-threatening arrhythmias (Page 9)
Recent reports show that ﬂ ecainide treatment completely prevents adrenergic-induced arrhythmias in a mouse model of CPVT and in humans with CSQ2 and RyR2 mutations (Page 10)
Lidocaine is another Na + blocker that does not inhibit RyR2 and has very low clinical effect on CPVT (Page 10)
ARVD is also a rare inherited disorder caused by RyR2 mutation located in same regions as CPVT and homologous with RyR1 mutations in MH and CCD (Page 10)
ARVD is characterized by substitution of the right ventricular myocardium with ﬁ brofatty tissue, which appears to be a result of progressive death of cardiomyo-cytes resulting from apoptosis and inﬂ ammation (Page 10)