Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cocaine use poses a major health problem not only because of the dependence it causes but also because of the generation of life-threatening cardiac arrhythmias following overdose. Elucidating the molecular mechanisms of action of cocaine, therefore, remains a critical step in developing treatment for cocaine addiction and preventing cardiac complications. Although the neurotransmitter transporters are suggested to be primary targets for cocaine, the continued drug-seeking behavior of transporter knock-out mice suggests the involvement of additional mechanisms. Several studies have shown that voltage-gated calcium channel blockers can prevent the behavioral and reinforcing effects of the drug and also cocaine-induced cardiac events, including lethal ventricular fibrillation. However, the role of voltage-gated calcium channels in cocaine-induced responses is not clear. Herein, I show that cocaine, in pharmacological doses, selectively and potently enhances L-type calcium channel currents in isolated rat ventricular myocytes. This potentiation by cocaine is due to an increase and decrease, respectively, in the calcium channel opening and closing rates, with no apparent effects on voltage-dependence or single-channel conductance. The effects of cocaine are rapidly reversible and unaffected by prior ATPgammaS-induced channel phosphorylation. These results suggest that cocaine directly binds and facilitates the opening of L-type calcium channels. Importantly, elevated intracellular calcium levels via this mechanism triggering second messenger pathways and gene activation may contribute to many of the cardiovascular and central nervous system effects of cocaine.
Mol Pharmacol 1999 Dec
PMID:Selective potentiation of L-type calcium channel currents by cocaine in cardiac myocytes. 1057 40

We used Northern analyses, RNase protection assays and immunoblot analyses to examine the relationship among developmental age of the heart, abundance of mRNA and L-type calcium channel alpha1C subunit protein, and to establish the size of the native protein in heart. Northern analysis, RNase protection assays, and immunoblots were used to study RNA and protein from rat heart of various ages. In fetal and adult ventricles there was a predominant 8.3-kb transcript for the alpha1C subunit with no change in transcript size during development. RNase protection assays demonstrated a 2-fold increase in abundance of the DHP receptor message during postnatal development. Immunoblots identified a 240 kD protein, corresponding to the predicted molecular mass of the full length alpha1C subunit. No change in size of protein for the alpha1C subunit was observed at any developmental stage and there was no evidence for a truncated isoform. There was an approximate 2-fold increase in alpha1C subunit protein in ventricular homogenates during postnatal development. Thus, in the developing rat heart, alterations in calcium channel properties during development appear to result neither from alternative splicing that produces a smaller transcript for the alpha1C subunit nor from expression of a truncated protein, but at least in part from transcriptionally-regulated expression of the 240 kDa polypepde.
Mol Cell Biochem 2000 Feb
PMID:Developmental regulation of the L-type calcium channel alpha1C subunit expression in heart. 1082 27

Recently suggested is an arguable hypothesis that neurotrophins can induce necrosis but suppress apoptosis of target cells in some pathological conditions. We examined this hypothesis by tracing the type of NGF-promoted cell death occurring in a hypoglycemic condition at various angles, such as kinetic analyses, histological examinations of membrane alterations, morphological observations in ultra-structural changes, and determinations of DNA fragmentation. Glucose-starved cell death consisted of two kinetically different stages, suggesting that it be mixed with early and delayed death. Several lines of evidence revealed that NGF prominently enhanced the early death with necrotic characters. By contrast, apoptotic characters of glucose-starved delayed death were not much affected by NGF. Nifedipine, a voltage-gated calcium channel blocker, could completely compensate for the enhancement of the early glucose-starved death by NGF. Interestingly, the NGF-promoted cell death was also blocked by cycloheximide that did not keep PC12 cells alive from glucose starvation. Therefore, all the data in this study suggest that NGF accelerates the early necrosis of glucose-starved cell death probably through the alterations of intracellular calcium ions and protein syntheses.
Mol Cells 2000 Aug 31
PMID:Potentiation of early necrotic death of glucose-starved pheochromocytoma 12 cells by nerve growth factor. 1098 43

The L-type calcium channel is a heteromultimeric protein complex, which is expressed in the cardiac sarcolemma. Although post-translational regulation of its subunits by protein kinase A (PKA) has been widely reported, little is known about molecular processes that regulate expression of calcium channel subunits (alpha(1C), alpha(2)- delta, and beta(2A)subunits). Previous studies from our group demonstrate that the steady-state mRNA level of the alpha(1C)unit is increased by treatment of myocytes with beta -adrenergic agonists. The current study is designed to determine whether the mRNA levels for all subunits of the L-type calcium channel are coordinately controlled by a beta -adrenergic agonist, and whether this occurs predominantly through control of rate of transcription. Nuclear run-on assays were used to determine the transcription initiation rate of these genes in cultured neonatal rat cardiac myocytes. In isoproterenol (10(-7)m)-treated myocytes, transcription of genes encoding the alpha(1C), alpha(2)- delta, and beta(2A)subunits was enhanced. The increases in transcription initiation rate for alpha(1C), alpha(2)- delta, and beta(2A)subunits genes were 404%, 367%, and 240% of control, respectively. Pretreatment with the beta -adrenergic antagonist propranolol (10(-5)m) or PKA inhibitor H-89 (10(-6)m) blocked the effects of isoproterenol, while either drug alone did not affect the gene transcription rate significantly. Steady state mRNA levels of the subunits increased following isoproterenol treatment. These results suggest that beta -adrenergic stimulation and the PKA signaling pathway play an important role in transcriptional regulation of the L-type calcium channel in myocyte. The expression of all the subunits of this ion channel is under coordinate transcriptional control.
J Mol Cell Cardiol 2000 Oct
PMID:Transcriptional regulation of L-type calcium channel expression in cardiac myocytes. 1101 28

Since the recognition of the importance of calcium ions to cardiac contractility, the effects of alterations in calcium homeostasis on cardiac myocyte function have attracted immense attention. However, the possibility that changes in extracellular calcium concentration or the administration of calcium channel blockers may exert significant effects on cardiac fibroblasts has not hitherto been explored. This communication presents evidence, for the first time, that EGTA, calcium-free incubation and L-type calcium channel blockers increase endogenous superoxide production in adult rat cardiac fibroblasts. A combination of ryanodine and EGTA was found to have an even greater effect. The observations indicate that extracellular calcium levels influence endogenous superoxide production in cardiac fibroblasts and support the postulation that myocardial fibroblasts may contribute to the cardiac effects of calcium channel blockers and alterations in extracellular calcium concentration.
J Mol Cell Cardiol 2001 Feb
PMID:L-type calcium channel blockers and EGTA enhance superoxide production in cardiac fibroblasts. 1116 40

Velo-cardio-facial syndrome (VCFS) has been associated with schizophrenic symptoms in some patients and is caused by a deletion of 22q11.21--q11.23. The voltage-gated calcium channel (VGCC) gamma 2 subunit is located on chromosome 22 and is telemeric to the most commonly observed VCFS deletion region but is near a putative marker for schizophrenia (D22S278). Metaphase spreads of four controls, four patients with VCFS, and one patient with VCFS and schizophrenia were evaluated for the VCFS deletion using the VCFS-diagnostic probe, TUPLE 1, and for deletion of VGCC gamma 2 subunit gene using probes for that gene's exon 1 and exons 3 and 4. All of the VCFS patients had deletion of the TUPLE 1 probe on one chromosome of the chromosome 22 pair. None showed deletion of the gamma 2 subunit exons studied. The location of the gamma 2 subunit gene at 22q13.1 was confirmed by FISH in all cases. This study did not show a deletion of the gamma 2 subunit gene as a distinguishing feature of our patient with VCFS and schizophrenia.
Mol Psychiatry 2001 Jul
PMID:Voltage-gated calcium channel gamma 2 subunit gene is not deleted in velo-cardio-facial syndrome. 1144 34

Congenital heart block (CHB) affects offspring of mothers with autoantibodies (positive IgG) to intracellular SSA/Ro and SSB/La ribonucleoproteins and is associated with high morbidity and mortality. Here, we show that maternal anti-Ro/La antibodies immunoreact with human fetal cardiomyocyte sarcolemma, recognize human L-type Ca channel alpha(1C)-protein and functionally inhibit expressed current in oocytes injected with alpha(1C) cRNA and Purkinje L-type Ca current. Furthermore, cardiac myocytes from pups born to SSA/Ro-immunized mice exhibited reduced L-type Ca current density. All together, the data establish that L-type calcium channel is a target for maternal antibodies and may provide a functional basis for the electrocardiographic abnormalities seen in infants with CHB.
J Mol Cell Cardiol 2001 Jun
PMID:Autoantibodies from mothers of children with congenital heart block downregulate cardiac L-type Ca channels. 1144 20

Calcium channel blocker is useful for a variety of purposes and is effective for preventing hepatitis elicited by different inducers, suggesting its possible clinical application for treating hepatitis. The alpha1-subunit of the dihydropyridine-sensitive L-type calcium channel is a target of calcium channel blocker. For clinical application of calcium channel blocker, it is important to analyze the expression of the L-type calcium channel in the liver. However, the subtype of the L-type calcium channel alpha1-subunit expressed in the liver was not known. In the present study, the alpha1-subunit of the calcium channel expressed in human liver was systematically analyzed. The alpha1D subunit of the dihydropyridine-sensitive L-type voltage gated calcium channel is expressed relatively strongly in the liver and may play an important role in the liver.
Int J Mol Med 2001 Oct
PMID:Expression of the alpha1D subunit of the L-type voltage gated calcium channel in human liver. 1156 80

Although an increase in the excitability and ectopic spontaneous discharge (ESD) of primary sensory neurons can lead to abnormal burst activity, which is associated with neuropathic pain, the underlying molecular mechanisms are not fully understood. To investigate the relationship between these electrical abnormalities in injured neurons and voltage-gated calcium channel (VGCC) gene expression, reverse transcription-polymerase chain reaction (RT-PCR) was used to monitor the expression of the VGCC alpha(1) gene in the dorsal root ganglion (DRG) following chronic constriction injury (CCI) and axotomy of the rat sciatic nerve. Electrophoresis of the RT-PCR products showed the presence of multiple types of VGCC alpha(1) transcripts with various levels of basal expression in lumbar 4, 5, and 6 DRGs. CCI decreased alpha(1C), alpha(1D), alpha(1H), and alpha(1I) mRNA expression at 7 days in the ipsilateral DRG, to approximately 34-50% of the contralateral side. The same transcripts were repressed 7 days after sciatic axotomy and their reduction levels proved similar to those of CCI. Considering that changes of the intracellular calcium concentration modify the maintenance of ESD in injured DRG, these results suggest that the downregulation of alpha(1C), alpha(1D), alpha(1H) and alpha(1I) subunit gene expression in the rat DRG following peripheral nerve injury may contribute to the production of ESD associated with damaged nerves.
Brain Res Mol Brain Res 2001 Nov 30
PMID:Changes in voltage-gated calcium channel alpha(1) gene expression in rat dorsal root ganglia following peripheral nerve injury. 1173 Oct 20

We have synthesized a novel series of 18 dialkyl 1,4-dihydro-4-(2'alkoxy-6'-pentadecylphenyl)-2,6-dimethyl-3,5 pyridine dicarboxylates from anacardic acid, a natural compound found in cashew nut shells, and investigated their blocking action on L- and T-type calcium channels transiently expressed in tSA-201 cells. The IC(50) values for L-type calcium channel block obtained with the series ranged from 1 to approximately 40 microM, with higher affinities being favored by increasing the size of the alkoxy group on the 4-phenyl ring and ester substituent in the 3,5 positions. A detailed analysis of the strongest L-type channel blocker of the series (PPK-12) revealed that block was poorly reversible and mediated an apparent speeding of the time course of inactivation. Moreover, in the presence of PPK-12, the midpoint of the steady state inactivation curve was shifted by 20 mV toward more hyperpolarized potentials, resulting in an increase in blocking efficacy at more depolarized holding potentials. Surprisingly, PPK-12 blocked T- and L-type calcium channels with similar affinities. One of the weakest L-type channel inhibitors (PPK-5) exhibited a T-type channel affinity that was similar to that seen with PPK-12, resulting in a 40-fold selectivity of PPK-5 for T- over L-type channels. Thus, dialkyl 1,4-dihydro-4-(2'alkoxy-6'-pentadecylphenyl)-2,6-dimethyl-3,5 pyridine dicarboxylates may serve as excellent candidates for the development of T-type calcium-channel specific blockers.
Mol Pharmacol 2002 Mar
PMID:Synthesis and evaluation of a new class of nifedipine analogs with T-type calcium channel blocking activity. 1185 46


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