scholarly journals Disruption of the IS6-AID Linker Affects Voltage-gated Calcium Channel Inactivation and Facilitation

2009 ◽  
Vol 133 (3) ◽  
pp. 327-343 ◽  
Author(s):  
Felix Findeisen ◽  
Daniel L. Minor
Keyword(s):  
Calcium Channel ◽  
Common Mechanism ◽  
Interaction Domain ◽  
Voltage Gated ◽  
Calcium Dependent ◽  
Calcium Channel Inactivation ◽  
Dependent Inactivation ◽  
Voltage Dependent ◽  
Rigid Connection ◽  
Voltage Gated Calcium Channel

Two processes dominate voltage-gated calcium channel (CaV) inactivation: voltage-dependent inactivation (VDI) and calcium-dependent inactivation (CDI). The CaVβ/CaVα1-I-II loop and Ca2+/calmodulin (CaM)/CaVα1–C-terminal tail complexes have been shown to modulate each, respectively. Nevertheless, how each complex couples to the pore and whether each affects inactivation independently have remained unresolved. Here, we demonstrate that the IS6–α-interaction domain (AID) linker provides a rigid connection between the pore and CaVβ/I-II loop complex by showing that IS6-AID linker polyglycine mutations accelerate CaV1.2 (L-type) and CaV2.1 (P/Q-type) VDI. Remarkably, mutations that either break the rigid IS6-AID linker connection or disrupt CaVβ/I-II association sharply decelerate CDI and reduce a second Ca2+/CaM/CaVα1–C-terminal–mediated process known as calcium-dependent facilitation. Collectively, the data strongly suggest that components traditionally associated solely with VDI, CaVβ and the IS6-AID linker, are essential for calcium-dependent modulation, and that both CaVβ-dependent and CaM-dependent components couple to the pore by a common mechanism requiring CaVβ and an intact IS6-AID linker.

scholarly journals A Selectivity Filter Gate Controls Voltage-Gated Calcium Channel Calcium-Dependent Inactivation

Neuron ◽  
2019 ◽  
Vol 101 (6) ◽  
pp. 1134-1149.e3 ◽  
Author(s):  
Fayal Abderemane-Ali ◽  
Felix Findeisen ◽  
Nathan D. Rossen ◽  
Daniel L. Minor
Keyword(s):  
Calcium Channel ◽  
Selectivity Filter ◽  
Voltage Gated ◽  
Calcium Dependent ◽  
Dependent Inactivation ◽  
Voltage Gated Calcium Channel

scholarly journals Single-Channel Mechanism of Modulation of Calcium-Dependent Inactivation of the Voltage-Gated Calcium Channel Cav1.3 by its C-Terminus

2013 ◽  
Vol 104 (2) ◽  
pp. 459a
Author(s):  
Elena Novikova ◽  
Elza Kuzmenkina ◽  
Wanchana Jangsangthong ◽  
Jan Matthes ◽  
Alexandra Koschak ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Single Channel ◽  
Voltage Gated ◽  
Calcium Dependent ◽  
C Terminus ◽  
Dependent Inactivation ◽  
Voltage Gated Calcium Channel

scholarly journals The structural biology of voltage-gated calcium channel function and regulation

2006 ◽  
Vol 34 (5) ◽  
pp. 887-893 ◽  
Author(s):  
F. Van Petegem ◽  
D.L. Minor
Keyword(s):  
Neurotransmitter Release ◽  
Action Potentials ◽  
Molecular Switches ◽  
Voltage Gated ◽  
Calcium Dependent ◽  
Voltage Gated Calcium Channels ◽  
Dependent Inactivation ◽  
Voltage Dependent ◽  
Soluble Calcium ◽  
Molecular Framework

Voltage-gated calcium channels (CaVs) are large (∼0.5 MDa), multisubunit, macromolecular machines that control calcium entry into cells in response to membrane potential changes. These molecular switches play pivotal roles in cardiac action potentials, neurotransmitter release, muscle contraction, calcium-dependent gene transcription and synaptic transmission. CaVs possess self-regulatory mechanisms that permit them to change their behaviour in response to activity, including voltage-dependent inactivation, calcium-dependent inactivation and calcium-dependent facilitation. These processes arise from the concerted action of different channel domains with CaV β-subunits and the soluble calcium sensor calmodulin. Until recently, nothing was known about the CaV structure at high resolution. Recent crystallographic work has revealed the first glimpses at the CaV molecular framework and set a new direction towards a detailed mechanistic understanding of CaV function.

scholarly journals Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel

2018 ◽  
Vol 115 (45) ◽  
pp. E10556-E10565 ◽  
Author(s):  
Kaiqian Wang ◽  
Christian Holt ◽  
Jocelyn Lu ◽  
Malene Brohus ◽  
Kamilla Taunsig Larsen ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Conformational Changes ◽  
Structural Changes ◽  
Voltage Gated ◽  
Cardiac Ion Channels ◽  
Disease Mutations ◽  
Dependent Inactivation ◽  
Ef Hand ◽  
Voltage Gated Calcium Channel ◽  
Structural Insights

Calmodulin (CaM) represents one of the most conserved proteins among eukaryotes and is known to bind and modulate more than a 100 targets. Recently, several disease-associated mutations have been identified in theCALMgenes that are causative of severe cardiac arrhythmia syndromes. Although several mutations have been shown to affect the function of various cardiac ion channels, direct structural insights into any CaM disease mutation have been lacking. Here we report a crystallographic and NMR investigation of several disease mutant CaMs, linked to long-QT syndrome, in complex with the IQ domain of the cardiac voltage-gated calcium channel (CaV1.2). Surprisingly, two mutants (D95V, N97I) cause a major distortion of the C-terminal lobe, resulting in a pathological conformation not reported before. These structural changes result in altered interactions with the CaV1.2 IQ domain. Another mutation (N97S) reduces the affinity for Ca2+by introducing strain in EF hand 3. A fourth mutant (F141L) shows structural changes in the Ca2+-free state that increase the affinity for the IQ domain. These results thus show that different mechanisms underlie the ability of CaM disease mutations to affect Ca2+-dependent inactivation of the voltage-gated calcium channel.

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