Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Li, Li; Li, De Pei; Chen, Shao Rui; Chen, Jinjun; Hu, Hongzhen; Pan, Hui Lin

doi:10.1124/mol.114.095505

Cited by 18 publications

(21 citation statements)

References 47 publications

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“… Mancilla and Rojas, ; 2 Wu, ; 3 Edwards and Weston, ; 4 Rogawski and Barker, ; 5 Caballero et al, ; 6 Mergenthaler et al, ; 7 Ru et al, ; 8 Levite et al, ; 9 Hille, ; 10 Bruner et al, ; 11 Päsler et al, ; 12 Zünkler, ; 13 Duan et al, ; 14 Li et al, ; 15 Liu et al, ; 16 Tarr et al, .…”

Section: Methodsunclassified

Akinesia and freezing caused by Na⁺ leak‐current channel (NALCN) deficiency corrected by pharmacological inhibition of K⁺ channels and gap junctions

Kasap

Bonnett

Aamodt

et al. 2016

J of Comparative Neurology

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The Na leak-current channel (NALCN) regulates locomotion, respiration, and intellectual development. Previous work highlighted striking similarities between characteristic movement phenotypes of NALCN-deficient animals (Drosophila and Caenorhabditis elegans) and the major symptoms of Parkinson's disease and primary progressive freezing gait. We have discovered novel physiological connections between the NALCN, K channels, and gap junctions that mediate regulation of locomotion in C. elegans. Drugs that block K channels and gap junctions or that activate Ca channels significantly improve movement of NALCN-deficient animals. Loss-of-function of the NALCN creates an imbalance in ions, including K and Ca , that interferes with normal cycles of depolarization-repolarization. This work suggests new therapeutic strategies for certain human movement disorders. J. Comp. Neurol. 525:1109-1121, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Methodsunclassified

Akinesia and freezing caused by Na⁺ leak‐current channel (NALCN) deficiency corrected by pharmacological inhibition of K⁺ channels and gap junctions

Kasap

Bonnett

Aamodt

et al. 2016

J of Comparative Neurology

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“…After 24 h, we used PolyJet DNA In Vitro transfection reagent (SignaGen Laboratories, Gaithersburg, MD) to transiently transfect the cells with various combinations of Cav␣ 1 (Cav1.2, Cav2.1, or Cav2.2), ␣ 2 ␦1, and Cav␤ (Cav␤1-Cav␤4) subunits. The sources of cDNAs for rat Cav␣ 1 , ␣ 2 ␦1, and Cav␤ subunits were reported previously (27,28). A Cav2.2-V5 construct was made by inserting a rat Cav2.2 fragment into a pCDNA6 V5-FLAG vector using an In-Fusion HD Cloning Kit (Clontech, Palo Alto, CA).…”

Section: Methodsmentioning

confidence: 99%

“…The cell membrane capacitance and series resistance were electronically compensated. Signals were filtered at 1 kHz, digitized at 10 kHz, and acquired using the Pulse program (HEKA Instruments (27).…”

Section: Methodsmentioning

confidence: 99%

“…The voltage-dependent inactivation of N-type channels was assessed by using a series of pre-pulses from Ϫ90 to 10 mV for 500 ms followed by depolarization of the cell to 0 mV for 150 ms (27). Bath application of SNAP had no significant effect on voltage-dependent inactivation of N-type channels in HEK293 cells expressing Cav2.2 ϩ ␣2␦1 and Cav␤1, Cav␤3, or Cav␤4 (Fig.…”

Section: Differential Effects Of Snap On N-type P/q-type and L-typementioning

confidence: 99%

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Molecular Basis of Regulating High Voltage-Activated Calcium Channels by S-Nitrosylation

Zhou

Bavencoffe

Pan

2015

Journal of Biological Chemistry

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Nitric oxide (NO) is involved in a variety of physiological processes, such as vasoregulation and neurotransmission, and has a complex role in the regulation of pain transduction and synaptic transmission. We have shown previously that NO inhibits high voltage-activated Ca 2؉ channels in primary sensory neurons and excitatory synaptic transmission in the spinal dorsal horn. However, the molecular mechanism involved in this inhibitory action remains unclear. In this study, we investigated the role of S-nitrosylation in the NO regulation of high voltage-activated Ca 2؉ channels. The NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) rapidly reduced N-type currents when Cav2.2 was coexpressed with the Cav␤1 or Cav␤3 subunits in HEK293 cells. In contrast, SNAP only slightly inhibited P/Q-type and L-type currents reconstituted with various Cav␤ subunits. SNAP caused a depolarizing shift in voltage-dependent N-type channel activation, but it had no effect on Cav2.2 protein levels on the membrane surface. The inhibitory effect of SNAP on N-type currents was blocked by the sulfhydryl-specific modifying reagent methanethiosulfonate ethylammonium. Furthermore, the consensus motifs of S-nitrosylation were much more abundant in Cav2.2 than in Cav1.2 and Cav2.1. Site-directed mutagenesis studies showed that Cys-805, Cys-930, and Cys-1045 in the II-III intracellular loop, Cys-1835 and Cys-2145 in the C terminus of Cav2.2, and Cys-346 in the Cav␤3 subunit were nitrosylation sites mediating NO sensitivity of N-type channels. Our findings demonstrate that the consensus motifs of S-nitrosylation in cytoplasmically accessible sites are critically involved in post-translational regulation of N-type Ca 2؉ channels by NO. S-Nitrosylation mediates the feedback regulation of N-type channels by NO.High voltage-activated (HVA) Ca 2ϩ channels play obligatory roles in diverse physiological functions, including regulation of gene expression, synaptic transmission, and muscle contraction. These channels are heteromeric protein complexes composed of ␣ 1 , ␤, and ␣ 2 ␦ subunits (1, 2). The ␣ 1 subunit (Cav␣ 1 ) contains the channel pore and is the principal component of HVA Ca 2ϩ channels. Both Cav␣ 1 and cytosolic auxiliary ␤ subunits (Cav␤) carry out essential gating functions (1,3,4). Cav␣ 1 has the most drug-binding sites of the subunits, whereas Cav␤ is essential for regulating the surface expression of the channel complex (1).There exist several types of HVA Ca 2ϩ channels, including L-, N-, P/Q-, and R-types. L-type Ca 2ϩ channels are not only present in cardiac and smooth muscles but also expressed in neurons and endocrine cells where they regulate a multitude of processes, including the release of hormones and neurotransmitters and gene expression (5, 6). N-type channels are distributed in the brain and peripheral nervous system and are the major subtypes present in nociceptive dorsal root ganglion (DRG) 2 neurons (7-10). P/Q-type channels are involved in neurotransmitter release at synaptic terminals (11,12). The Cav␤ subunits (Cav␤...

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“…More recently, specific sites in the GK, HOOK and C-terminus domains of Ca v β 3 were identified, by a site-directed mutagenesis study as crucial for the potentiation of L-type and N-type currents by 4-AP [116]. Together, these findings indicate that 4-AP, as well as its analogues, are able to stimulate directly HVACC in neurons independently of K v channels through Ca v β 3 .…”

Section: Interaction Of Ca V β With Pharmacologically Active Moleculementioning

confidence: 92%

Protein partners of the calcium channel β subunit highlight new cellular functions

Rima

Daghsni

Fajloun

et al. 2016

Biochemical Journal

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Calcium plays a key role in cell signalling by its intervention in a wide range of physiological processes. Its entry into cells occurs mainly via voltage-gated calcium channels (VGCC), which are found not only in the plasma membrane of excitable cells but also in cells insensitive to electrical signals. VGCC are composed of different subunits, α1, β, α2δ and γ, among which the cytosolic β subunit (Cavβ) controls the trafficking of the channel to the plasma membrane, its regulation and its gating properties. For many years, these were the main functions associated with Cavβ. However, a growing number of proteins have been found to interact with Cavβ, emphasizing the multifunctional role of this versatile protein. Interestingly, some of the newly assigned functions of Cavβ are independent of its role in the regulation of VGCC, and thus further increase its functional roles. Based on the identity of Cavβ protein partners, this review emphasizes the diverse cellular functions of Cavβ and summarizes both past findings as well as recent progress in the understanding of VGCC.

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Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Cited by 18 publications

References 47 publications

Akinesia and freezing caused by Na⁺ leak‐current channel (NALCN) deficiency corrected by pharmacological inhibition of K⁺ channels and gap junctions

Akinesia and freezing caused by Na⁺ leak‐current channel (NALCN) deficiency corrected by pharmacological inhibition of K⁺ channels and gap junctions

Molecular Basis of Regulating High Voltage-Activated Calcium Channels by S-Nitrosylation

Protein partners of the calcium channel β subunit highlight new cellular functions

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Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Cited by 18 publications

References 47 publications

Akinesia and freezing caused by Na+ leak‐current channel (NALCN) deficiency corrected by pharmacological inhibition of K+ channels and gap junctions

Akinesia and freezing caused by Na+ leak‐current channel (NALCN) deficiency corrected by pharmacological inhibition of K+ channels and gap junctions

Molecular Basis of Regulating High Voltage-Activated Calcium Channels by S-Nitrosylation

Protein partners of the calcium channel β subunit highlight new cellular functions

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Akinesia and freezing caused by Na⁺ leak‐current channel (NALCN) deficiency corrected by pharmacological inhibition of K⁺ channels and gap junctions

Akinesia and freezing caused by Na⁺ leak‐current channel (NALCN) deficiency corrected by pharmacological inhibition of K⁺ channels and gap junctions