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Tymothy syndrome (TS) is a multisystem disorder featuring cardiac arrhythmias, autism and adrenal gland dysfunction that originates from a de-novo point-mutation in the gene encoding Cav1.2 (CACNA1C) L-type channel. To study the role of Cav1.2 channel signals on autism, the autistic TS2-neo mouse has been generated bearing the G406R point-mutation associated with TS type-2. Using heterozygous TS2-neo mice, we report that the G406R mutation reduces the rate of inactivation and shifts leftward the activation and inactivation of L-type channels, causing marked increase of resting Ca -influx ("window" Ca -current). The increased "window current" causes marked reduction of Na channel-density, switches normal tonic firing in abnormal burst firing, reduces mitochondria metabolism, induces cell swelling and decreases catecholamine release. Overnight incubations with nifedipine rescue Na channel-density, the normal firing and the quantity of catecholamine released. We provide evidence that chromaffin cells malfunction derives from altered Cav1.2 channel-gatings. L-type voltage-gated calcium channels (Cav1) have a key role in long-term synaptic plasticity, sensory transduction, muscle contraction and hormone release. A point mutation in the gene encoding Cav1.2 (CACNA1C) causes Tymothy syndrome (TS), a multisystem disorder featuring cardiac arrhythmias, autism spectrum disorder (ASD) and adrenal gland dysfunction. In the more severe type-2 form (TS2), the missense mutation G406R is on exon 8 coding for the IS6-helix of Cav1.2 channel. The mutation causes reduced inactivation and induces autism. How this occurs and how Cav1.2 gating-changes alter cell excitability, neuronal firing and hormone release on molecular basis is still widely unknown. Here, using the TS2-neo mouse model of Timothy syndrome we show that the G406R mutation alters excitability and reduces secretory activity in adrenal chromaffin cells (CCs). Specifically, the TS2-mutation reduces the rate of voltage-dependent inactivation and shifts leftward the activation and steady state inactivation of L-type channels. This markedly increases the resting "window" Ca current that causes an increased percentage of CCs undergoing abnormal action potential (AP) burst firing, cell swelling, reduced mitochondrial metabolism and decreased catecholamine release. The increased "window Ca -current" causes also decreased Na channel-density and increased steady-state inactivation that contribute to the increased abnormal burst firing. Overnight incubation with the L-type channel blocker nifedipine rescues the normal AP firing of CCs, the density of functioning Na channels and their steady-state inactivation. We provide evidence that CCs malfunction derives from the altered Cav1.2 channel gating and that dihydropyridines are potential therapeutics for ASD. This article is protected by copyright. All rights reserved.
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Name: The Journal of physiology
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Small bodies containing chromaffin cells occurring outside of the adrenal medulla, most commonly near the sympathetic ganglia and in organs such as the kidney, liver, heart and gonads.
Organelles in CHROMAFFIN CELLS located in the adrenal glands and various other organs. These granules are the site of the synthesis, storage, metabolism, and secretion of EPINEPHRINE and NOREPINEPHRINE.
Cells that store epinephrine secretory vesicles. During times of stress, the nervous system signals the vesicles to secrete their hormonal content. Their name derives from their ability to stain a brownish color with chromic salts. Characteristically, they are located in the adrenal medulla and paraganglia (PARAGANGLIA, CHROMAFFIN) of the sympathetic nervous system.
A disorder beginning in childhood. It is marked by the presence of markedly abnormal or impaired development in social interaction and communication and a markedly restricted repertoire of activity and interest. Manifestations of the disorder vary greatly depending on the developmental level and chronological age of the individual. (DSM-IV)
Measurable changes in activities in the CEREBRAL CORTEX upon a stimulation. A change in cortical excitability as measured by various techniques (e.g., TRANSCRANIAL MAGNETIC STIMULATION) is associated with brain disorders.
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