In:
The Journal of Physiology, Wiley, Vol. 597, No. 6 ( 2019-03), p. 1705-1733
Abstract:
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 the Cav1.2 ( CACNA1C ) L‐type channel. To study the role of Cav1.2 channel signals in 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 2+ influx (‘window’ Ca 2+ current). The increased ‘window current’ causes marked reduction of Na V channel density, switches normal tonic firing to abnormal burst firing, reduces mitochondrial metabolism, induces cell swelling and decreases catecholamine release. Overnight incubations with nifedipine rescue Na V channel density, normal firing and the quantity of catecholamine released. We provide evidence that chromaffin cell malfunction derives from altered Cav1.2 channel gating.
Type of Medium:
Online Resource
ISSN:
0022-3751
,
1469-7793
DOI:
10.1113/tjp.2019.597.issue-6
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
1475290-6
SSG:
12
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