Molecular Basis of an Inherited Epilepsy

Lossin, Christoph; Wang, Dao Wen; Rhodes, Thomas H.; Vanoye, Carlos G.; George, Alfred L.

doi:10.1016/s0896-6273(02)00714-6

Cited by 332 publications

(348 citation statements)

References 39 publications

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“…3D) were similar for hNa v 1.1 and M1841T. Persistent slowly inactivating Na ϩ current (INa P ) is important for neuron excitability and epileptogenic mutations can increase its amplitude (Lossin et al, 2002). We recorded INa P with 150-ms-long depolarizing steps to 0 mV (Fig.…”

Section: M1841t Does Not Alter the Main Functional Properties Of The mentioning

confidence: 83%

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Na_v1.1 Na⁺Channel Mutant

Rusconi¹,

Scalmani²,

Cassulini³

et al. 2007

J. Neurosci.

110

111

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Familial epilepsies are often caused by mutations of voltage-gated Na ϩ channels, but correlation genotype-phenotype is not yet clear. In particular, the cause of phenotypic variability observed in some epileptic families is unclear. We studied Na v 1.1 (SCN1A) Na ϩ channel ␣ subunit M1841T mutation, identified in a family characterized by a particularly large phenotypic spectrum. The mutant is a loss of function because when expressed alone, the current was no greater than background. Function was restored by incubation at temperature Ͻ30°C, showing that the mutant is trafficking defective, thus far the first case among neuronal Na ϩ channels. Importantly, also molecular interactions with modulatory proteins or drugs were able to rescue the mutant. Protein-protein interactions may modulate the effect of the mutation in vivo and thus phenotype; variability in their strength may be one of the causes of phenotypic variability in familial epilepsy. Interacting drugs may be used to rescue the mutant in vivo.

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Section: M1841t Does Not Alter the Main Functional Properties Of The mentioning

confidence: 83%

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Na_v1.1 Na⁺Channel Mutant

Rusconi¹,

Scalmani²,

Cassulini³

et al. 2007

J. Neurosci.

110

111

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“…Possibly this dominant effect relates to the ability of ADE generated from one gene copy to restrict the efficiency of DA clearance from a WT copy sufficiently to trigger functional effects. Inappropriately inactivated or tonic leak conductances lead to dominant effects for a number of disorders, including epilepsy (96) and paralytic disorders (97). An alternative mechanism for dominant effects could involve DAT multimers of mixed Ala559 and Val559 partners, although to date these interactions have not been documented in vivo (98,99).…”

Section: Discussionmentioning

confidence: 99%

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

Mergy¹,

Gowrishankar²,

Gresch

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

113

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Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPHevoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.T he neurotransmitter dopamine (DA) plays a key role in regulating brain circuits that control reward, attention, and locomotor activity (1-3), Accordingly, dopaminergic dysfunction is believed to contribute to several neuropsychiatric disorders including Parkinson's disease (4), bipolar disorder (BPD) (5), drug abuse and addiction (6), and attention-deficit hyperactivity disorder (ADHD) (7,8). The presynaptic DA transporter (DAT) is the primary mechanism for terminating DA signaling at the synapse (9) and is the primary target for several psychostimulant drugs including cocaine (COC), methylphenidate (MPH), and amphetamine (AMPH). COC and MPH are DAT antagonists, elevating extracellular DA levels by preventing DAT-mediated DA reuptake (10). AMPH actions are more complex (11). AMPH is structurally similar to DA and, as a result, is transported by DAT, competing with DA during the reuptake process. AMPH also induces DAT-mediated nonvesicular release, also termed "DA efflux," a process that involves the actions of intracellular signaling proteins such as CamKIIα (12-16) and , alterations in interactions with DAT-associated proteins and phospholipids (12,14,20), and changes in DAT phosphorylation (12,16,(21)(22)(23)) that biases the transporter toward an efflux-competent mechanism. Despite their mechanistic differences, MPH and AMPH both rapidly elevate DA in the CNS and are components of the most frequently prescribed medications for ADHD, Ritalin and Adderall, respectively. The DA modulatory actions of MPH and AMPH reinforce hypotheses derived from brain imaging studies (24) and the analysis of common genetic variation (25-30)...

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“…The functional consequences of these mutations in expression systems have proven to be diverse, and not simply related to enhanced excitability, although some enhance persistent current. 41 Computer simulations, however, suggest that the changes can explain increased neuronal firing. 42 Two other severe syndromes of early life are associated with mutations in SCN1A.…”

Section: Voltage-gated Sodium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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Molecular Basis of an Inherited Epilepsy

Cited by 332 publications

References 39 publications

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Na_v1.1 Na⁺Channel Mutant

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Na_v1.1 Na⁺Channel Mutant

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

Molecular Targets for Antiepileptic Drug Development

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Molecular Basis of an Inherited Epilepsy

Cited by 332 publications

References 39 publications

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+Channel Mutant

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+Channel Mutant

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

Molecular Targets for Antiepileptic Drug Development

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Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Na_v1.1 Na⁺Channel Mutant

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Na_v1.1 Na⁺Channel Mutant