RESUMEN
Background: In 2017, a provincial guideline was created to fast track and standardize care for pediatric appendicitis in Alberta. We conducted a study to determine the impact of implementation of the guideline at our institution on length of stay (LOS), antibiotic stewardship efforts and costs. Methods: We performed a retrospective review of the charts of all patients younger than 18 years of age who underwent appendectomy at our institution in 2 periods: before guideline implementation (Dec. 1, 2016, to May 31, 2017) and after implementation (Dec. 1, 2017, to May 31, 2018). We compared LOS, duration of antibiotic therapy, 30-day postdischarge complication rates and variable cost between the 2 cohorts. Results: Of the 276 total appendectomy procedures performed, 185 were for simple appendicitis (81 before guideline implementation and 104 after implementation), and 91 were for complicated appendicitis (44 and 47, respectively). The median LOS was shorter in the postimplementation cohort for both simple and complicated appendicitis (15.5 h [interquartile range (IQR) 12-19 h] v. 17.0 h [IQR 13-22 h], p = 0.03; and 3.0 d [IQR 2-4 d] v. 3.0 d [IQR 3-5 d], p = 0.05, respectively). Patients with complicated appendicitis had fewer antibiotic days after guideline implementation; the difference was statistically significant for patients without diffuse peritoneal contamination or abscess formation (p = 0.02). There were no differences between the cohorts with respect to 30-day rates of complications, including emergency department visits, readmission and surgical site infections. After guideline implementation, the average variable cost per patient was reduced by $230, equating to a total average annual cost savings of $75 842 for our institution. Conclusion: The implementation of a provincial guideline aimed at standardizing care in pediatric appendicitis at our institution was associated with shortened LOS, improved antibiotic stewardship efforts and reduced cost of care. Other institutions may replicate our model of a standardized pathway in the management of pediatric appendicitis in an effort to improve the quality of patient care and reduce health care costs.
Contexte: En 2017, des lignes directrices provinciales ont vu le jour en Alberta afin d'accélérer et de normaliser les soins pédiatriques pour appendicite. Notre étude visait à déterminer l'effet de leur application, par notre établissement, sur la durée du séjour, la gestion des antibiotiques et les coûts des soins. Méthodes: Nous avons examiné de façon rétrospective le dossier de tous les patients de moins de 18 ans ayant subi une appendicectomie à notre établissement avant l'application des lignes directrices (entre le 1er décembre 2016 et le 31 mai 2017) et après (entre le 1er décembre 2017 et le 31 mai 2018). Les données relatives à la durée du séjour, à la durée de l'antibiothérapie, au taux de complications 30 jours après le congé et aux coûts variables ont été comparées entre les 2 groupes. Résultats: Des 276 appendicectomies totales effectuées, 185 concernaient une appendicite simple (81 avant l'application des lignes directrices et 104 après), et 91, une appendicite compliquée (44 avant l'application et 47 après). La durée médiane du séjour était plus courte dans le groupe postapplication, tant pour l'appendicite simple (15,5 h [écart interquartile (EI) 1219 h] c. 17,0 h [EI 1322 h]; p = 0,03) que pour l'appendicite compliquée (3,0 j [EI 24 j] c. 3,0 j [EI 35 j]; p = 0,05). Les patients qui présentaient une appendicite compliquée avaient une antibiothérapie moins longue après l'application des lignes directrices; la différence était statistiquement significative chez les patients sans contamination péritonéale diffuse ou abcès (p = 0,02). Aucune différence n'a été observée entre les cohortes en ce qui a trait au taux de complications à 30 jours, qui comprenait les consultations à l'urgence, les réadmissions et les infections du site opératoire. L'application des lignes directrices a permis de réduire les coûts variables par patient de 230 $, ce qui représente une économie annuelle moyenne de 75 842 $ pour notre établissement. Conclusion: L'application des lignes directrices provinciales visant à normaliser les soins pédiatriques pour appendicite a été associée, dans notre établissement, à une réduction de la durée du séjour, à l'amélioration de la gestion des antibiotiques et à une diminution des coûts des soins. D'autres établissements pourraient reproduire ce modèle de soins normalisés pour améliorer la qualité et réduire les coûts.
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Apendicitis/economía , Apendicitis/terapia , Protocolos Clínicos , Guías de Práctica Clínica como Asunto , Alberta , Antibacterianos/uso terapéutico , Programas de Optimización del Uso de los Antimicrobianos , Apendicectomía , Niño , Femenino , Humanos , Tiempo de Internación , Masculino , Pediatría , Estudios RetrospectivosRESUMEN
OBJECTIVE: To describe the development of the Pediatric Epilepsy Outcome-Informatics Project (PEOIP) at Alberta Children's Hospital (ACH), which was created to provide standardized, point-of-care data entry; near-time data analysis; and availability of outcome dashboards as a baseline on which to pursue quality improvement. METHODS: Stakeholders involved in the PEOIP met weekly to determine the most important outcomes for patients diagnosed with epilepsy, create a standardized electronic note with defined fields (patient demographics, seizure and syndrome type and frequency and specific outcomes- seizure type and frequency, adverse effects, emergency department visits, hospitalization, and care pathways for clinical decision support. These were embedded in the electronic health record from which the fields were extracted into a data display platform that provided patient- and population-level dashboards updated every 36 hours. Provider satisfaction and family experience surveys were performed to assess the impact of the standardized electronic note. RESULTS: In the last 5 years, 3,245 unique patients involving 13, 831 encounters had prospective, longitudinal, standardized epilepsy data accrued via point-of-care data entry into an electronic note as part of routine clinical care. A provider satisfaction survey of the small number of users involved indicated that the vast majority believed that the note makes documentation more efficient. A family experience survey indicated that being provided with the note was considered "valuable" or "really valuable" by 86% of respondents and facilitated communication with family members, school, and advocacy organizations. SIGNIFICANCE: The PEOIP serves as a proof of principle that information obtained as part of routine clinical care can be collected in a prospective, standardized, efficient manner and be used to construct filterable process/outcome dashboards, updated in near time (36 hours). This information will provide the necessary baseline data on which multiple of QI projects to improve meaningful outcomes for children with epilepsy will be based.
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Registros Electrónicos de Salud , Epilepsia , Niño , Documentación , Epilepsia/terapia , Humanos , Estudios Prospectivos , Mejoramiento de la CalidadRESUMEN
Calmodulin (CaM) is an important signaling molecule that regulates a vast array of cellular functions by activating second messengers involved in cell function and plasticity. Low voltage-activated calcium channels of the Cav3 family have the important role of mediating low threshold calcium influx, but were not believed to interact with CaM. We find a constitutive association between CaM and the Cav3.1 channel at rest that is lost through an activity-dependent and Cav3.1 calcium-dependent CaM dissociation. Moreover, Cav3 calcium influx is sufficient to activate αCaMKII in the cytoplasm in a manner that depends on an intact Cav3.1 C-terminus needed to support the CaM interaction. Our findings thus establish that T-type channel calcium influx invokes a novel dynamic interaction between CaM and Cav3.1 channels to trigger a signaling cascade that leads to αCaMKII activation.
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Canales de Calcio Tipo T/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Calmodulina/metabolismo , Animales , Calcio/metabolismo , Activación Enzimática , Transferencia Resonante de Energía de Fluorescencia , Humanos , Inmunoprecipitación , Ratones Endogámicos C57BL , Neuronas/metabolismo , Fosforilación , Agregado de Proteínas , Ratas Sprague-DawleyRESUMEN
The L-type voltage-gated calcium channel Cav1.2 and the calcium-activated CaM kinase cascade both regulate excitation transcription coupling in the brain. CaM kinase is known to associate with the C terminus of Cav1.2 in a region called the PreIQ-IQ domain, which also binds multiple calmodulin molecules. Here we identify and characterize a second CaMKII binding site in the N terminus of Cav1.2 that is formed by a stretch of four amino residues (cysteine-isoleucine-serine-isoleucine) and which regulates channel expression and function. By using live cell imaging of tsA-201 cells we show that GFP fusion constructs of the CaMKII binding region, termed N2B-II co-localize with mCherry-CaMKII. Mutating CISI to AAAA ablates binding to and colocalization with CaMKII. Cav1.2-AAAA channels show reduced cell surface expression in tsA-201 cells, but interestingly, display an increase in channel function that offsets the trafficking deficit. Altogether our data reveal that the proximal N terminus of Cav1.2 contains a CaMKII binding region which contributes to channel surface expression and function.
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Canales de Calcio Tipo L/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Potenciales de Acción , Secuencia de Aminoácidos , Animales , Sitios de Unión , Canales de Calcio Tipo L/química , Membrana Celular/metabolismo , Células HEK293 , Humanos , Datos de Secuencia Molecular , Unión Proteica , Transporte de Proteínas , RatasRESUMEN
BACKGROUND: The L-type calcium channel Cav1.2 is important for brain and heart function. The ubiquitous calcium sensing protein calmodulin (CaM) regulates calcium dependent gating of Cav1.2 channels by reducing calcium influx, a process known as calcium-dependent inactivation (CDI). Dissecting the calcium-dependence of CaM in this process has benefited greatly from the use of mutant CaM molecules which are unable to bind calcium to their low affinity (N-lobe) and high affinity (C-lobe) binding sites. Unlike CDI, it is unknown whether CaM can modulate the activation gating of Cav1.2 channels. RESULTS: We examined a Cav1.2 point mutant in the N-terminus region of the channel (A39V) that has been previously linked to Brugada syndrome. Using mutant CaM constructs in which the N- and/or C-lobe calcium binding sites were ablated, we were able to show that this Brugada syndrome mutation disrupts N-lobe CDI of the channel. In the course of these experiments, we discovered that all mutant CaM molecules were able to alter the kinetics of channel activation even in the absence of calcium for WT-Cav1.2, but not A39V-Cav1.2 channels. Moreover, CaM mutants differentially shifted the voltage-dependence of activation for WT and A39V-Cav1.2 channels to hyperpolarized potentials. Our data therefore suggest that structural changes in CaM that arise directly from site directed mutagenesis of calcium binding domains alter activation gating of Cav1.2 channels independently of their effects on calcium binding, and that the N-terminus of the channel contributes to this CaM dependent process. CONCLUSIONS: Our data indicate that caution must be exercised when interpreting the effects of CaM mutants on ion channel gating.
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Sustitución de Aminoácidos , Síndrome de Brugada/genética , Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/metabolismo , Calmodulina/metabolismo , Mutación/genética , Animales , Calcio/farmacología , Canales de Calcio Tipo L/química , Humanos , Activación del Canal Iónico/efectos de los fármacos , Cinética , Proteínas Mutantes/metabolismo , Unión Proteica/efectos de los fármacos , RatasRESUMEN
Voltage-gated calcium channels are the primary mediators of depolarization-induced calcium entry into neurons. There is great diversity of calcium channel subtypes due to multiple genes that encode calcium channel α1 subunits, coassembly with a variety of ancillary calcium channel subunits, and alternative splicing. This allows these channels to fulfill highly specialized roles in specific neuronal subtypes and at particular subcellular loci. While calcium channels are of critical importance to brain function, their inappropriate expression or dysfunction gives rise to a variety of neurological disorders, including, pain, epilepsy, migraine, and ataxia. This Review discusses salient aspects of voltage-gated calcium channel function, physiology, and pathophysiology.
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Encefalopatías , Canales de Calcio/metabolismo , Neuronas/fisiología , Animales , Encefalopatías/metabolismo , Encefalopatías/patología , Encefalopatías/fisiopatología , Canales de Calcio/química , Canales de Calcio/clasificación , Canales de Calcio/genética , HumanosRESUMEN
The L-type voltage-gated calcium channel Cav1.2 is important for excitation-contraction coupling in the heart, as well as CREB-mediated transcription in the brain. The ubiquitous calcium-binding protein calmodulin (CaM) is known to modulate calcium-dependent inactivation (CDI) of these channels, thus limiting the amount of calcium entering via Cav1.2 during prolonged or repetitive membrane depolarizations. The proximal N-terminus of Cav1.2 contains a CaM-binding site at residue W52 that is critical for a type of CDI that is mediated by the N-terminal lobe of CaM. Here, we identify a second CaM interaction site in the Cav1.2 N-terminus downstream of the W52 site that is formed by residue C106. We show by site-directed mutagenesis coupled with electrophysiological measurements that this region of the channel functionally partakes in N-lobe CDI, likely by acting as a gating transduction motif. Thus, our data indicate that calcium regulation of Cav1.2 channels is more complex than previously thought, and involves more than one region within the channel's N-terminal domain.
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Canales de Calcio Tipo L/metabolismo , Calcio/metabolismo , Calmodulina/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Sitios de Unión/fisiología , Línea Celular , Humanos , Immunoblotting , Microscopía Confocal , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Técnicas de Placa-Clamp , Estructura Terciaria de Proteína , Ratas , TransfecciónRESUMEN
BACKGROUND: A loss of function of the L-type calcium channel, Cav1.2, results in a cardiac specific disease known as Brugada syndrome. Although many Brugada syndrome channelopathies reduce channel function, one point mutation in the N-terminus of Cav1.2 (A39V) has been shown to elicit disease a phenotype because of a loss of surface trafficking of the channel. This lack of cell membrane expression could not be rescued by the trafficking chaperone Cavß. FINDINGS: We report that despite the striking loss of trafficking described previously in the cardiac Cav1.2 channel, the A39V mutation while in the background of the brain isoform traffics and functions normally. We detected no differences in biophysical properties between wild type Cav1.2 and A39V-Cav1.2 in the presence of either a cardiac (Cavß2b), or a neuronal beta subunit (Cavß1b). In addition, the A39V-Cav1.2 mutant showed a normal Cavß2b mediated increase in surface expression in tsA-201 cells. CONCLUSIONS: The Brugada syndrome mutation A39V when introduced into rat brain Cav1.2 does not trigger the loss-of-trafficking phenotype seen in a previous study on the human heart isoform of the channel.
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Sustitución de Aminoácidos/genética , Síndrome de Brugada/genética , Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/metabolismo , Membrana Celular/metabolismo , Mutación/genética , Neuronas/metabolismo , Secuencia de Aminoácidos , Animales , Canales de Calcio Tipo L/química , Línea Celular , Humanos , Datos de Secuencia Molecular , Ratas , Alineación de SecuenciaRESUMEN
Voltage-gated calcium channels are important mediators of calcium influx into electrically excitable cells. The amount of calcium entering through this family of channel proteins is not only determined by the functional properties of channels embedded in the plasma membrane but also by the numbers of channels that are expressed at the cell surface. The trafficking of channels is controlled by numerous processes, including co-assembly with ancillary calcium channel subunits, ubiquitin ligases, and interactions with other membrane proteins such as G protein coupled receptors. Here we provide an overview about the current state of knowledge of calcium channel trafficking to the cell membrane, and of the mechanisms regulating the stability and internalization of this important ion channel family.
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Canales de Calcio/metabolismo , Animales , Canales de Calcio/química , Calmodulina/fisiología , Membrana Celular/metabolismo , Humanos , Subunidades de Proteína/química , Subunidades de Proteína/metabolismo , Transporte de ProteínasRESUMEN
It is well established that the auxiliary Cavß subunit regulates calcium channel density in the plasma membrane, but the cellular mechanism by which this occurs has remained unclear. We found that the Cavß subunit increased membrane expression of Cav1.2 channels by preventing the entry of the channels into the endoplasmic reticulum-associated protein degradation (ERAD) complex. Without Cavß, Cav1.2 channels underwent robust ubiquitination by the RFP2 ubiquitin ligase and interacted with the ERAD complex proteins derlin-1 and p97, culminating in targeting of the channels to the proteasome for degradation. On treatment with the proteasomal inhibitor MG132, Cavß-free channels were rescued from degradation and trafficked to the plasma membrane. The coexpression of Cavß interfered with ubiquitination and targeting of the channel to the ERAD complex, thereby facilitating export from the endoplasmic reticulum and promoting expression on the cell surface. Thus, Cavßß regulates the ubiquitination and stability of the calcium channel complex.
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Canales de Calcio Tipo L/metabolismo , Proteínas de Unión al ADN/metabolismo , Retículo Endoplásmico/metabolismo , Neuronas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Subunidades de Proteína/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Ubiquitinación/fisiología , Análisis de Varianza , Animales , Western Blotting , Canales de Calcio Tipo L/genética , Células Cultivadas , Proteínas de Unión al ADN/genética , Retículo Endoplásmico/genética , Ensayo de Inmunoadsorción Enzimática , Hipocampo/citología , Hipocampo/metabolismo , Inmunohistoquímica , Inmunoprecipitación , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Microscopía Confocal , Neuronas/citología , Complejo de la Endopetidasa Proteasomal/genética , Subunidades de Proteína/genética , Ratas , Factor 2 Asociado a Receptor de TNF , Transfección , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genética , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/metabolismo , Proteínas Supresoras de Tumor/genética , Ubiquitina/genética , Ubiquitina/metabolismoRESUMEN
We have generated a syntaxin 1A knockout mouse by deletion of exons 3 through 6 and a concomitant insertion of a stop codon in exon 2. Heterozygous knockout animals were viable with no apparent phenotype. In contrast, the vast majority of homozygous animals died in utero, with embryos examined at day E15 showing a drastic reduction in body size and development when compared to WT and heterozygous littermates. Surprisingly, out of a total of 204 offspring from heterozygous breeding pairs only four homozygous animals were born alive and viable. These animals exhibited reduced body weight, but showed only mild behavioral deficiencies. Taken together, our data indicate that syntaxin 1A is an important regulator of normal in utero development, but may not be essential for normal brain function later in life.
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Desarrollo Embrionario , Muerte Fetal , Sintaxina 1/fisiología , Útero/fisiología , Animales , Codón de Terminación/genética , Desarrollo Embrionario/genética , Exones/genética , Femenino , Muerte Fetal/genética , Peso Fetal/genética , Humanos , Ratones , Ratones Noqueados , Ratas , Eliminación de Secuencia , Sintaxina 1/genéticaRESUMEN
When transiently expressed in tsA-201 cells, Ca(v)1.4 calcium channels support only modest whole-cell currents with unusually slow voltage-dependent inactivation kinetics. To examine the basis for this unique behavior we used cell-attached patch single-channel recordings using 100 mM external barium as the charge carrier to determine the single-channel properties of Ca(v)1.4 and to compare them to those of the Ca(v)1.2. Ca(v)1.4 channel openings occurred infrequently and were of brief duration. Moreover, openings occurred throughout the duration of the test depolarization, indicating that the slow inactivation kinetics observed at the whole-cell level are caused by sustained channel activity. Ca(v)1.4 and Ca(v)1.2 channels displayed similar latencies to first opening. Because of the rare occurrence of events, the probability of opening could not be precisely determined but was estimated to be <0.015 over a voltage range of -20 to +20 mV. The single-channel conductance of Ca(v)1.4 channels was approximately 4 pS compared with approximately 20 pS for Ca(v)1.2 under the same experimental conditions. Additionally, in the absence of divalent cations, Ca(v)1.4 channels pass cesium ions with a single-channel conductance of approximately 21 pS. Although Ca(v)1.2 opening events were best described kinetically with two open time constants, Ca(v)1.4 open times were best described by a single time constant. BayK8644 slightly enhanced the single-channel conductance in addition to increasing the open time constant for Ca(v)1.4 channels by approximately 45% without, however, causing the appearance of an additional slower gating mode. Overall, our data indicate that single Ca(v)1.4 channels support only minute amounts of calcium entry, suggesting that large numbers of these channels are needed to allow for significant whole-cell current activity, and providing a mechanism to reduce noise in the visual system.
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Biofisica/métodos , Secuencia de Aminoácidos , Animales , Canales de Calcio/química , Canales de Calcio Tipo L/química , Línea Celular Tumoral , Clonación Molecular , ADN/química , ADN Complementario/metabolismo , Electrofisiología , Ácido Glutámico/química , Humanos , Cinética , Datos de Secuencia Molecular , Probabilidad , Estructura Terciaria de Proteína , ARN/química , Ratas , Homología de Secuencia de Aminoácido , Factores de Tiempo , TransfecciónRESUMEN
The modulation of N-type calcium channels is a key factor in the control of neurotransmitter release. Whereas N-type channels are inhibited by Gbetagamma subunits in a G protein beta-isoform-dependent manner, channel activity is typically stimulated by activation of protein kinase C (PKC). In addition, there is cross-talk among these pathways, such that PKC-dependent phosphorylation of the Gbetagamma target site on the N-type channel antagonizes subsequent G protein inhibition, albeit only for Gbeta(1)-mediated responses. The molecular mechanisms that control this G protein beta subunit subtype-specific regulation have not been described. Here, we show that G protein inhibition of N-type calcium channels is critically dependent on two separate but adjacent approximately 20-amino acid regions of the Gbeta subunit, plus a highly conserved Asn-Tyr-Val motif. These regions are distinct from those implicated previously in Gbetagamma signaling to other effectors such as G protein-coupled inward rectifier potassium channels, phospholipase beta(2), and adenylyl cyclase, thus raising the possibility that the specificity for G protein signaling to calcium channels might rely on unique G protein structural determinants. In addition, we identify a highly specific locus on the Gbeta(1) subunit that serves as a molecular detector of PKC-dependent phosphorylation of the G protein target site on the N-type channel alpha(1) subunit, thus providing for a molecular basis for G protein-PKC cross-talk. Overall, our results significantly advance our understanding of the molecular details underlying the integration of G protein and PKC signaling pathways at the level of the N-type calcium channel alpha(1) subunit.
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Canales de Calcio Tipo N/metabolismo , Subunidades beta de la Proteína de Unión al GTP/metabolismo , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Isoformas de Proteínas/metabolismo , Proteína Quinasa C/metabolismo , Subunidades de Proteína/metabolismo , Transducción de Señal/fisiología , Secuencia de Aminoácidos , Animales , Línea Celular , Subunidades beta de la Proteína de Unión al GTP/química , Subunidades beta de la Proteína de Unión al GTP/genética , Proteínas de Unión al GTP Heterotriméricas/química , Proteínas de Unión al GTP Heterotriméricas/genética , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Técnicas de Placa-Clamp , Estructura Terciaria de Proteína , Ratas , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Alineación de SecuenciaRESUMEN
Childhood absence epilepsy (CAE) is a type of generalized epilepsy observed in 2-10% of epileptic children. In a recent study by Chen et al. (Chen, Y., Lu, J., Pan, H., Zhang, Y., Wu, H., Xu, K., Liu, X., Jiang, Y., Bao, X., Yao, Z., Ding, K., Lo, W. H., Qiang, B., Chan, P., Shen, Y., and Wu, X. (2003) Ann. Neurol. 54, 239-243) 12 missense mutations were identified in the CACNA1H (Ca(v)3.2) gene in 14 of 118 patients with CAE but not in 230 control individuals. We have functionally characterized five of these mutations (F161L, E282K, C456S, V831M, and D1463N) using rat Ca(v)3.2 and whole-cell patch clamp recordings in transfected HEK293 cells. Two of the mutations, F161L and E282K, mediated an approximately 10-mV hyperpolarizing shift in the half-activation potential. Mutation V831M caused a approximately 50% slowing of inactivation relative to control and shifted half-inactivation potential approximately 10 mV toward more depolarized potentials. Mean time to peak was significantly increased by mutation V831M but was unchanged for all others. No resolvable changes in the parameters of the IV relation or current kinetics were observed with the remaining mutations. The findings suggest that several of the Ca(v)3.2 mutants allow for greater calcium influx during physiological activation and in the case of F161L and E282K can result in channel openings at more hyperpolarized (close to resting) potentials. This may underlie the propensity for seizures in patients with CAE.