Disease relevance of Cacng2

• The Cacng2 gene is disrupted in the stargazer mouse, with its distinctive phenotype including ataxia, frequent absence seizure episodes, and head elevation [1].
• The stg/stg mutant phenotype confirms the general principal that inherited epilepsies sharing similar cortical excitability patterns can be transmitted by single gene loci residing on different chromosomes and provides new evidence that the severity of seizure expression depends on the specific mutant gene affected [2].
• These results suggest that the defect in MF to GC synaptic transmission is a major factor that causes the cerebellar dysfunction in the stg mutant mouse [3].
• Limited sequence homology to stargazin, a cerebellar synapse four-transmembrane-domain protein, suggests a role for clarin-1 in hair cell and photoreceptor cell synapses, as well as a common pathophysiological pathway for different Usher syndromes [4].

High impact information on Cacng2

• Stargazer mice have spike-wave seizures characteristic of absence epilepsy, with accompanying defects in the cerebellum and inner ear [5].
• The anticipated effect in stargazer mutants, inappropriate Ca2+ entry, may contribute to their more pronounced seizure phenotype compared with other mouse absence models with Ca2+-channel defects [5].
• It encodes a 36-kD protein (stargazin) with structural similarity to the gamma subunit of skeletal muscle voltage-gated calcium (Ca2+) channels [5].
• Stargazin is brain-specific and, like other neuronal Ca2+-channel subunits, is enriched in synaptic plasma membranes [5].
• In vitro, stargazin increases steady-state inactivation of alpha1 class A Ca2+ channels [5].

Chemical compound and disease context of Cacng2

• Pharmacological profiles of generalized absence seizures in lethargic, stargazer and gamma-hydroxybutyrate-treated model mice [6].
• We examined the pharmacological profiles of generalized absence seizures in three mouse models: two mutant strains with spontaneous absence seizures, lethargic and stargazer, and ddY mice (GHB model) in which absence seizures were induced by administering gamma-butyrolactone (GBL), a prodrug of gamma-hydroxybutyric acid (GHB) [6].
• The roles of the stargazin protein in calcium channel function and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor trafficking are discussed; focus is placed on studies regarding the thalamus, whence absence seizures potentially originate, and the cerebellum, which is associated with the ataxic phenotype [7].

Biological context of Cacng2

• All three mutations affect the Cacng2 mRNA levels as they all arise from disruptions within the introns of this gene [8].
• Absence of cerebellar granule cell BDNF mRNA in stg/stg mice demonstrates that sustained expression of this neurotrophin is not required for cell survival in the developing cerebellar cortex [9].
• The data suggest that the cell adhesion function of stargazin preceded its current role in neurons as a regulator of either voltage-dependent calcium channels or AMPA receptors [10].
• Here, we report that expression of stargazin in mouse L-fibroblasts results in cell aggregation comparable with that produced by claudins, and present evidence that the interaction is heterotypic and calcium dependent [10].
• Intracellular and whole cell recordings from stg/stg neurons in deep layers showed spontaneous giant depolarizing excitatory post-synaptic potentials generating bursts of action potentials, and a 78% reduction in the afterburst hyperpolarization [11].

Anatomical context of Cacng2

• Aberrant GABA(A) receptor expression in the dentate gyrus of the epileptic mutant mouse stargazer [12].
• The expression levels of synapsins were not altered in stg cerebellum, but showed a significant upregulation in stg cerebral cortex and hippocampus [13].
• Quantitative measurement showed a significantly lower number of synapses and smaller area of presynaptic terminals in adult stg cerebellum when compared with age-matched wildtype [13].
• Total specific [3H]Ro15-4513 binding activity detected in cerebellar membranes prepared from stg/stg was not significantly different from +/+ mice [14].
• Immunoblotting analysis of the SNARE proteins revealed selective reduction of the levels of synaptobrevin and synaptophysin in synaptosomes from stg cerebellum [13].

Associations of Cacng2 with chemical compounds

• We established that the alpha4 betagamma2 subunit-containing, flunitrazepam-insensitive subtype of GABARs, not normally a significant GABAR in DG neurons, was strongly upregulated in stg DG, apparently arising at the expense of extrasynaptic alpha4 betadelta-containing receptors [12].
• Functional studies suggest a dual role for stargazin, both as a modulatory gamma subunit for voltage-dependent calcium channels and as a regulator of post-synaptic membrane targeting for alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors [10].
• The sensitivity of stg mutant GCs to exogenously applied AMPA was greatly reduced, whereas that to NMDA was unchanged [3].
• However, it is unclear whether the trafficking of kainate receptors, which are structurally very similar to AMPA receptors, is also dependent on stargazin [15].
• Cerebellar Golgi, Purkinje, and basket cells have reduced gamma-aminobutyric acid immunoreactivity in stargazer mutant mice [16].

Regulatory relationships of Cacng2

• Genetic analysis of stargazer mice determined that the defective gene encodes a protein expressed in brain (gamma2) with limited homology to the skeletal muscle L-type calcium channel gamma1 subunit [17].

Other interactions of Cacng2

• To test this hypothesis, the targeted Cacng4 mutation was combined with alleles of Cacng2 [1].
• Phenotype of cerebellar glutamatergic neurons is altered in stargazer mutant mice lacking brain-derived neurotrophic factor mRNA expression [18].
• A comparative analysis of channel function and neural excitability patterns in tottering, lethargic, and stargazer brain should be useful in identifying the common elements of calcium channel involvement in these absence models [19].
• The mutation was identified in the gamma 2 subunit gene of the high voltage-dependent calcium channel, Cacng2 [8].
• The extreme C terminus of stargazin (sequence, -TTPV), confers high affinity for PDZ domain-containing proteins e.g. PSD-95 [20].

Analytical, diagnostic and therapeutic context of Cacng2

• Co-immunoprecipitation experiments demonstrate that stargazin can bind proteins of either complex in vivo, but it remains unclear whether it can associate with both complexes simultaneously [10].
• We report here the initial description of the inheritance pattern, linkage mapping, and electroclinical phenotype of a recessive mutation on mouse Chromosome 15, stargazer (stg), that produces epilepsy [2].
• Electroencephalographic (EEG) analysis confirmed that stargazer has frequent spike-wave discharges (SWDs); the average duration of each discharge burst is 5 seconds and recurs every minute [8].

References