Identification of a molecular gating determinant within the carboxy terminal region of Cav3.3 T-type channels

  title={Identification of a molecular gating determinant within the carboxy terminal region of Cav3.3 T-type channels},
  author={Bohumila Jurkovicova-Tarabova and Leos Cmarko and Renata Rehak and Gerald W. Zamponi and Ľubica Lacinov{\'a} and Norbert Weiss},
  journal={Molecular Brain},
The physiological functions controlled by T-type channels are intrinsically dependent on their gating properties, and alteration of T-type channel activity is linked to several human disorders. Therefore, it is essential to develop a clear understanding of the structural determinants responsible for the unique gating features of T-type channels. Here, we have investigated the specific role of the carboxy terminal region by creating a series a deletion constructs expressed in tsA-201 cells and… 

Selective inhibition of neuronal Cav3.3 T-type calcium channels by TAT-based channel peptide

The ability of a TAT-based cell penetrating peptide containing this carboxy proximal region (TAT-C3P) to modulate the activity of Cav3 channels is explored and it is shown that chronic application of Tat-C4P on tsA-201 cells expressing Cav3 channel selectively inhibits Cav3.3 channels.

Electrophysiological and computational analysis of Cav3.2 channel variants associated with familial trigeminal neuralgia

The present study adds to the notion that ion channel polymorphisms could contribute to the etiology of some cases of TN and further support a role for Cav3.2 channels.

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

The newly identified ΔI153 variant is the first to be reported to cause a complete loss of Cav3.2 channel function, adding to the notion that loss-of-function of Cav 3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.

Analysing an allelic series of rare missense variants of CACNA1I in a Swedish schizophrenia cohort

The functional analysis of an allelic series of >50 CACNA1I variants in a schizophrenia cohort reveal that loss of function of CaV3.3 is a molecular phenotype associated with reduced disease risk burden, and this approach may serve as a template strategy for channelopathies in polygenic disorders.

Compound heterozygous CACNA1H mutations associated with severe congenital amyotrophy

Functional analysis of Cav3.2 variants revealed several alterations of the gating properties of the channel that were in general consistent with a loss-of-channel function, suggesting that severe congenital amyoplasia may be related to CACNA1H and would represent a new phenotype associated with mutations in this gene.



I–II Loop Structural Determinants in the Gating and Surface Expression of Low Voltage-Activated Calcium Channels

These experiments enrich the understanding of the structural determinants involved in Cav3 function by highlighting the unique role played by the intracellular I–II loop in Cav 3.2 channel trafficking, and illustrating the prominent role of the gating brake in setting the slow and distinctive slow activation kinetics of Cav3.3.

Molecular characterization of a neuronal low-voltage-activated T-type calcium channel

Based on the channel's distinctive voltage dependence, slow deactivation kinetics, and 7.5-pS single-channel conductance, it is concluded that this channel is a low-voltage-activated T-type calcium channel.

T-type calcium channels: From molecule to therapeutic opportunities.

Gating Kinetics of the α1i T-Type Calcium Channel

The α1I T-type calcium channel inactivates almost 10-fold more slowly than the other family members (α1G and α1H) or most native T-channels, and its gating mechanism can be described by the same kinetic scheme used for α1G, where voltage sensor movement is allosterically coupled to inactivation.

A Cav3.2/Syntaxin-1A Signaling Complex Controls T-type Channel Activity and Low-threshold Exocytosis*

These findings provide compelling evidence for the existence of a syntaxin-1A/T-type Ca2+ channel signaling complex and provide new insights into the molecular mechanism by which these channels control low-threshold exocytosis.

Cloning and Expression of a Novel Member of the Low Voltage-Activated T-Type Calcium Channel Family

It is suggested that α1I plays important roles in determining the electroresponsiveness of neurons, and hence, may be a novel drug target.

The amino side of the C‐terminus determines fast inactivation of the T‐type calcium channel α1G

A putative ‘ball‐and‐chain’‐like mechanism for inactivation in which the negative charges function as an acceptor domain for a ball, hypothetically located at a different intracellular part of the channel.