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Genetic interactions found between calcium channel genes modulate amyloid load measured by positron emission tomography.
Koran ME, Hohman TJ, Thornton-Wells TA
(2014) Hum Genet 133: 85-93
MeSH Terms: Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Apolipoprotein E4, Brain, Calcium Channels, L-Type, Chromosome Mapping, Epistasis, Genetic, Female, Genotype, Homeostasis, Humans, Male, Polymorphism, Single Nucleotide, Positron-Emission Tomography, Reproducibility of Results, Ryanodine Receptor Calcium Release Channel
Show Abstract · Added December 10, 2014
Late-onset Alzheimer's disease (LOAD) is known to have a complex, oligogenic etiology, with considerable genetic heterogeneity. We investigated the influence of genetic interactions between genes in the Alzheimer's disease (AD) pathway on amyloid-beta (Aβ) deposition as measured by PiB or AV-45 ligand positron emission tomography (PET) to aid in understanding LOAD's genetic etiology. Subsets of the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts were used for discovery and for two independent validation analyses. A significant interaction between RYR3 and CACNA1C was confirmed in all three of the independent ADNI datasets. Both genes encode calcium channels expressed in the brain. The results shown here support previous animal studies implicating interactions between these calcium channels in amyloidogenesis and suggest that the pathological cascade of this disease may be modified by interactions in the amyloid-calcium axis. Future work focusing on the mechanisms of such relationships may inform targets for clinical intervention.
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18 MeSH Terms
Inhibition of the late sodium current slows t-tubule disruption during the progression of hypertensive heart disease in the rat.
Aistrup GL, Gupta DK, Kelly JE, O'Toole MJ, Nahhas A, Chirayil N, Misener S, Beussink L, Singh N, Ng J, Reddy M, Mongkolrattanothai T, El-Bizri N, Rajamani S, Shryock JC, Belardinelli L, Shah SJ, Wasserstrom JA
(2013) Am J Physiol Heart Circ Physiol 305: H1068-79
MeSH Terms: Acetanilides, Animals, Calcium Channels, L-Type, Calcium Signaling, Disease Models, Animal, Disease Progression, Dose-Response Relationship, Drug, Heart Failure, Hypertension, Hypertrophy, Left Ventricular, Male, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel, Piperazines, Ranolazine, Rats, Rats, Inbred SHR, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Sodium, Sodium Channel Blockers, Sodium Channels, Sodium-Calcium Exchanger, Time Factors, Ultrasonography
Show Abstract · Added February 28, 2014
The treatment of heart failure (HF) is challenging and morbidity and mortality are high. The goal of this study was to determine if inhibition of the late Na(+) current with ranolazine during early hypertensive heart disease might slow or stop disease progression. Spontaneously hypertensive rats (aged 7 mo) were subjected to echocardiographic study and then fed either control chow (CON) or chow containing 0.5% ranolazine (RAN) for 3 mo. Animals were then restudied, and each heart was removed for measurements of t-tubule organization and Ca(2+) transients using confocal microscopy of the intact heart. RAN halted left ventricular hypertrophy as determined from both echocardiographic and cell dimension (length but not width) measurements. RAN reduced the number of myocytes with t-tubule disruption and the proportion of myocytes with defects in intracellular Ca(2+) cycling. RAN also prevented the slowing of the rate of restitution of Ca(2+) release and the increased vulnerability to rate-induced Ca(2+) alternans. Differences between CON- and RAN-treated animals were not a result of different expression levels of voltage-dependent Ca(2+) channel 1.2, sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a, ryanodine receptor type 2, Na(+)/Ca(2+) exchanger-1, or voltage-gated Na(+) channel 1.5. Furthermore, myocytes with defective Ca(2+) transients in CON rats showed improved Ca(2+) cycling immediately upon acute exposure to RAN. Increased late Na(+) current likely plays a role in the progression of cardiac hypertrophy, a key pathological step in the development of HF. Early, chronic inhibition of this current slows both hypertrophy and development of ultrastructural and physiological defects associated with the progression to HF.
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25 MeSH Terms
L-type calcium channels play a critical role in maintaining lens transparency by regulating phosphorylation of aquaporin-0 and myosin light chain and expression of connexins.
Maddala R, Nagendran T, de Ridder GG, Schey KL, Rao PV
(2013) PLoS One 8: e64676
MeSH Terms: Animals, Aquaporins, Calcium Channel Blockers, Calcium Channels, L-Type, Connexins, Eye Proteins, Felodipine, Female, Gene Expression, Immunoblotting, Lens, Crystalline, Male, Mice, Mice, Inbred C57BL, Myosin Light Chains, Nifedipine, Phosphorylation, Reverse Transcriptase Polymerase Chain Reaction, beta-Crystallin B Chain
Show Abstract · Added May 27, 2014
Homeostasis of intracellular calcium is crucial for lens cytoarchitecture and transparency, however, the identity of specific channel proteins regulating calcium influx within the lens is not completely understood. Here we examined the expression and distribution profiles of L-type calcium channels (LTCCs) and explored their role in morphological integrity and transparency of the mouse lens, using cDNA microarray, RT-PCR, immunoblot, pharmacological inhibitors and immunofluorescence analyses. The results revealed that Ca (V) 1.2 and 1.3 channels are expressed and distributed in both the epithelium and cortical fiber cells in mouse lens. Inhibition of LTCCs with felodipine or nifedipine induces progressive cortical cataract formation with time, in association with decreased lens weight in ex-vivo mouse lenses. Histological analyses of felodipine treated lenses revealed extensive disorganization and swelling of cortical fiber cells resembling the phenotype reported for altered aquaporin-0 activity without detectable cytotoxic effects. Analysis of both soluble and membrane rich fractions from felodipine treated lenses by SDS-PAGE in conjunction with mass spectrometry and immunoblot analyses revealed decreases in β-B1-crystallin, Hsp-90, spectrin and filensin. Significantly, loss of transparency in the felodipine treated lenses was preceded by an increase in aquaporin-0 serine-235 phosphorylation and levels of connexin-50, together with decreases in myosin light chain phosphorylation and the levels of 14-3-3ε, a phosphoprotein-binding regulatory protein. Felodipine treatment led to a significant increase in gene expression of connexin-50 and 46 in the mouse lens. Additionally, felodipine inhibition of LTCCs in primary cultures of mouse lens epithelial cells resulted in decreased intracellular calcium, and decreased actin stress fibers and myosin light chain phosphorylation, without detectable cytotoxic response. Taken together, these observations reveal a crucial role for LTCCs in regulation of expression, activity and stability of aquaporin-0, connexins, cytoskeletal proteins, and the mechanical properties of lens, all of which have a vital role in maintaining lens function and cytoarchitecture.
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19 MeSH Terms
Triadin regulates cardiac muscle couplon structure and microdomain Ca(2+) signalling: a path towards ventricular arrhythmias.
Chopra N, Knollmann BC
(2013) Cardiovasc Res 98: 187-91
MeSH Terms: Animals, Calcium Channels, L-Type, Calcium Signaling, Calsequestrin, Carrier Proteins, Excitation Contraction Coupling, Humans, Membrane Microdomains, Muscle Proteins, Myocytes, Cardiac, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum, Tachycardia, Ventricular
Show Abstract · Added February 12, 2015
Since the discovery of triadin >20 years ago as one of the major proteins located in the junctional sarcoplasmic reticulum, the field has come a long way in understanding the pivotal role of triadin in orchestrating sarcoplasmic reticulum Ca(2+)-release and hence excitation-contraction (EC) coupling. Building on the information gathered from earlier lipid bilayer and myocyte overexpression studies, the gene-targeted ablation of Trdn demonstrated triadin's indispensable role for maintaining the structural integrity of the couplon. More recently, the discovery of inherited and acquired diseases displaying altered expression and function of triadin has further emphasized the role of triadin in health and disease. Novel therapeutic approaches could be aimed at correcting the loss of triadin in diseased hearts, and thereby correcting the sub-cellular EC coupling defect. This review summarizes current concepts of the impact of triadin on cardiac EC coupling with a focus towards triadin's role for ventricular arrhythmia.
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13 MeSH Terms
G protein modulation of CaV2 voltage-gated calcium channels.
Currie KP
(2010) Channels (Austin) 4: 497-509
MeSH Terms: Animals, Calcium Channels, Calcium Channels, L-Type, Calcium Channels, P-Type, Calcium Channels, Q-Type, Calcium Signaling, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Humans, Ion Channel Gating, Membrane Potentials, Models, Molecular, Protein Conformation, Receptors, G-Protein-Coupled, Structure-Activity Relationship
Show Abstract · Added March 30, 2013
Voltage-gated Ca(2+) channels translate the electrical inputs of excitable cells into biochemical outputs by controlling influx of the ubiquitous second messenger Ca(2+) . As such the channels play pivotal roles in many cellular functions including the triggering of neurotransmitter and hormone release by CaV2.1 (P/Q-type) and CaV2.2 (N-type) channels. It is well established that G protein coupled receptors (GPCRs) orchestrate precise regulation neurotransmitter and hormone release through inhibition of CaV2 channels. Although the GPCRs recruit a number of different pathways, perhaps the most prominent, and certainly most studied among these is the so-called voltage-dependent inhibition mediated by direct binding of Gβγ to the α1 subunit of CaV2 channels. This article will review the basics of Ca(2+) -channels and G protein signaling, and the functional impact of this now classical inhibitory mechanism on channel function. It will also provide an update on more recent developments in the field, both related to functional effects and crosstalk with other signaling pathways, and advances made toward understanding the molecular interactions that underlie binding of Gβγ to the channel and the voltage-dependence that is a signature characteristic of this mechanism.
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15 MeSH Terms
CaV1.2 beta-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations.
Koval OM, Guan X, Wu Y, Joiner ML, Gao Z, Chen B, Grumbach IM, Luczak ED, Colbran RJ, Song LS, Hund TJ, Mohler PJ, Anderson ME
(2010) Proc Natl Acad Sci U S A 107: 4996-5000
MeSH Terms: Action Potentials, Animals, Binding Sites, Calcium, Calcium Channels, L-Type, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cell Death, Cell Membrane, Enzyme Activation, Ion Channel Gating, Leucine, Models, Biological, Mutant Proteins, Myocytes, Cardiac, Phosphorylation, Protein Binding, Protein Subunits, Rabbits, Sarcoplasmic Reticulum, Structure-Activity Relationship, Threonine
Show Abstract · Added March 20, 2014
Excessive activation of calmodulin kinase II (CaMKII) causes arrhythmias and heart failure, but the cellular mechanisms for CaMKII-targeted proteins causing disordered cell membrane excitability and myocardial dysfunction remain uncertain. Failing human cardiomyocytes exhibit increased CaMKII and voltage-gated Ca(2+) channel (Ca(V)1.2) activity, and enhanced expression of a specific Ca(V)1.2 beta-subunit protein isoform (beta(2a)). We recently identified Ca(V)1.2 beta(2a) residues critical for CaMKII phosphorylation (Thr 498) and binding (Leu 493), suggesting the hypothesis that these amino acids are crucial for cardiomyopathic consequences of CaMKII signaling. Here we show WT beta(2a) expression causes cellular Ca(2+) overload, arrhythmia-triggering cell membrane potential oscillations called early afterdepolarizations (EADs), and premature death in paced adult rabbit ventricular myocytes. Prevention of intracellular Ca(2+) release by ryanodine or global cellular CaMKII inhibition reduced EADs and improved cell survival to control levels in WT beta(2a)-expressing ventricular myocytes. In contrast, expression of beta(2a) T498A or L493A mutants mimicked the protective effects of ryanodine or global cellular CaMKII inhibition by reducing Ca(2+) entry through Ca(V)1.2 and inhibiting EADs. Furthermore, Ca(V)1.2 currents recorded from cells overexpressing CaMKII phosphorylation- or binding-incompetent beta(2a) subunits were incapable of entering a CaMKII-dependent high-activity gating mode (mode 2), indicating that beta(2a) Thr 498 and Leu 493 are required for Ca(V)1.2 activation by CaMKII in native cells. These data show that CaMKII binding and phosphorylation sites on beta(2a) are concise but pivotal components of a molecular and biophysical and mechanism for EADs and impaired survival in adult cardiomyocytes.
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21 MeSH Terms
Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC.
Jeon D, Kim S, Chetana M, Jo D, Ruley HE, Lin SY, Rabah D, Kinet JP, Shin HS
(2010) Nat Neurosci 13: 482-8
MeSH Terms: Animals, Calcium Channels, L-Type, Cerebral Cortex, Conditioning, Classical, Fear, Female, Freezing Reaction, Cataleptic, Gyrus Cinguli, Learning, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pain, Pain Measurement, Protein Subunits, Rats, Rats, Sprague-Dawley, Social Behavior
Show Abstract · Added May 29, 2014
Fear can be acquired vicariously through social observation of others suffering from aversive stimuli. We found that mice (observers) developed freezing behavior by observing other mice (demonstrators) receive repetitive foot shocks. Observers had higher fear responses when demonstrators were socially related to themselves, such as siblings or mating partners. Inactivation of anterior cingulate cortex (ACC) and parafascicular or mediodorsal thalamic nuclei, which comprise the medial pain system representing pain affection, substantially impaired this observational fear learning, whereas inactivation of sensory thalamic nuclei had no effect. The ACC neuronal activities were increased and synchronized with those of the lateral amygdala at theta rhythm frequency during this learning. Furthermore, an ACC-limited deletion of Ca(v)1.2 Ca(2+) channels in mice impaired observational fear learning and reduced behavioral pain responses. These results demonstrate the functional involvement of the affective pain system and Ca(v)1.2 channels of the ACC in observational social fear.
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19 MeSH Terms
CaMKII associates with CaV1.2 L-type calcium channels via selected beta subunits to enhance regulatory phosphorylation.
Abiria SA, Colbran RJ
(2010) J Neurochem 112: 150-61
MeSH Terms: Animals, Calcium Channels, L-Type, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cell Line, Humans, Mice, Mice, Inbred C57BL, Phosphorylation, Prosencephalon, Protein Binding, Protein Subunits, Rabbits, Rats, Rats, Sprague-Dawley
Show Abstract · Added June 21, 2013
Calcium/calmodulin-dependent kinase II (CaMKII) facilitates L-type calcium channel (LTCC) activity physiologically, but may exacerbate LTCC-dependent pathophysiology. We previously showed that CaMKII forms stable complexes with voltage-gated calcium channel (VGCC) beta(1b) or beta(2a) subunits, but not with the beta(3) or beta(4) subunits (Grueter et al. 2008). CaMKII-dependent facilitation of Ca(V)1.2 LTCCs requires Thr498 phosphorylation in the beta(2a) subunit (Grueter et al. 2006), but the relationship of this modulation to CaMKII interactions with LTCC subunits is unknown. Here we show that CaMKII co-immunoprecipitates with forebrain LTCCs that contain Ca(V)1.2alpha(1) and beta(1) or beta(2) subunits, but is not detected in LTCC complexes containing beta(4) subunits. CaMKIIalpha can be specifically tethered to the I/II linker of Ca(V)1.2 alpha(1) subunits in vitro by the beta(1b) or beta(2a) subunits. Efficient targeting of CaMKIIalpha to the full-length Ca(V)1.2alpha(1) subunit in transfected HEK293 cells requires CaMKII binding to the beta(2a) subunit. Moreover, disruption of CaMKII binding substantially reduced phosphorylation of beta(2a) at Thr498 within the LTCC complex, without altering overall phosphorylation of Ca(V)1.2alpha(1) and beta subunits. These findings demonstrate a biochemical mechanism underlying LTCC facilitation by CaMKII.
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14 MeSH Terms
Ablation of triadin causes loss of cardiac Ca2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias.
Chopra N, Yang T, Asghari P, Moore ED, Huke S, Akin B, Cattolica RA, Perez CF, Hlaing T, Knollmann-Ritschel BE, Jones LR, Pessah IN, Allen PD, Franzini-Armstrong C, Knollmann BC
(2009) Proc Natl Acad Sci U S A 106: 7636-41
MeSH Terms: Animals, Arrhythmias, Cardiac, Calcium, Calcium Channels, L-Type, Carrier Proteins, Heart, Intracellular Signaling Peptides and Proteins, Mice, Mice, Mutant Strains, Muscle Proteins, Myocardial Contraction, Myocardium, Sarcoplasmic Reticulum, Sequence Deletion
Show Abstract · Added May 27, 2014
Heart muscle excitation-contraction (E-C) coupling is governed by Ca(2+) release units (CRUs) whereby Ca(2+) influx via L-type Ca(2+) channels (Cav1.2) triggers Ca(2+) release from juxtaposed Ca(2+) release channels (RyR2) located in junctional sarcoplasmic reticulum (jSR). Although studies suggest that the jSR protein triadin anchors cardiac calsequestrin (Casq2) to RyR2, its contribution to E-C coupling remains unclear. Here, we identify the role of triadin using mice with ablation of the Trdn gene (Trdn(-/-)). The structure and protein composition of the cardiac CRU is significantly altered in Trdn(-/-) hearts. jSR proteins (RyR2, Casq2, junctin, and junctophilin 1 and 2) are significantly reduced in Trdn(-/-) hearts, whereas Cav1.2 and SERCA2a remain unchanged. Electron microscopy shows fragmentation and an overall 50% reduction in the contacts between jSR and T-tubules. Immunolabeling experiments show reduced colocalization of Cav1.2 with RyR2 and substantial Casq2 labeling outside of the jSR in Trdn(-/-) myocytes. CRU function is impaired in Trdn(-/-) myocytes, with reduced SR Ca(2+) release and impaired negative feedback of SR Ca(2+) release on Cav1.2 Ca(2+) currents (I(Ca)). Uninhibited Ca(2+) influx via I(Ca) likely contributes to Ca(2+) overload and results in spontaneous SR Ca(2+) releases upon beta-adrenergic receptor stimulation with isoproterenol in Trdn(-/-) myocytes, and ventricular arrhythmias in Trdn(-/-) mice. We conclude that triadin is critically important for maintaining the structural and functional integrity of the cardiac CRU; triadin loss and the resulting alterations in CRU structure and protein composition impairs E-C coupling and renders hearts susceptible to ventricular arrhythmias.
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14 MeSH Terms
A model of action potentials and fast Ca2+ dynamics in pancreatic beta-cells.
Fridlyand LE, Jacobson DA, Kuznetsov A, Philipson LH
(2009) Biophys J 96: 3126-39
MeSH Terms: Action Potentials, Adenosine Triphosphate, Animals, Calcium, Calcium Channels, L-Type, Calcium Signaling, Cell Membrane, Computer Simulation, Delayed Rectifier Potassium Channels, Glucose, Insulin-Secreting Cells, Mice, Mice, Knockout, Models, Neurological, Patch-Clamp Techniques, Potassium, Potassium Channels, Voltage-Gated, Shab Potassium Channels, Sodium, Tetraethylammonium, Time
Show Abstract · Added February 12, 2015
We examined the ionic mechanisms mediating depolarization-induced spike activity in pancreatic beta-cells. We formulated a Hodgkin-Huxley-type ionic model for the action potential (AP) in these cells based on voltage- and current-clamp results together with measurements of Ca(2+) dynamics in wild-type and Kv2.1 null mouse islets. The model contains an L-type Ca(2+) current, a "rapid" delayed-rectifier K(+) current, a small slowly-activated K(+) current, a Ca(2+)-activated K(+) current, an ATP-sensitive K(+) current, a plasma membrane calcium-pump current and a Na(+) background current. This model, coupled with an equation describing intracellular Ca(2+) homeostasis, replicates beta-cell AP and Ca(2+) changes during one glucose-induced spontaneous spike, the effects of blocking K(+) currents with different inhibitors, and specific complex spike in mouse islets lacking Kv2.1 channels. The currents with voltage-independent gating variables can also be responsible for burst behavior. Original features of this model include new equations for L-type Ca(2+) current, assessment of the role of rapid delayed-rectifier K(+) current, and Ca(2+)-activated K(+) currents, demonstrating the important roles of the Ca(2+)-pump and background currents in the APs and bursts. This model provides acceptable fits to voltage-clamp, AP, and Ca(2+) concentration data based on in silico analysis.
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21 MeSH Terms