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Article ; Online: Disease causing mutations of calcium channels.

Lorenzon, Nancy M / Beam, Kurt G

2008 Volume 2, Issue 3, Page(s) 163–179

Abstract: Calcium ions play an important role in the electrical excitability of nerve and muscle, as well as serving as a critical second messenger for diverse cellular functions. As a result, mutations of genes encoding calcium channels may have subtle affects on ...

Abstract	Calcium ions play an important role in the electrical excitability of nerve and muscle, as well as serving as a critical second messenger for diverse cellular functions. As a result, mutations of genes encoding calcium channels may have subtle affects on channel function yet strongly perturb cellular behavior. This review discusses the effects of calcium channel mutations on channel function, the pathological consequences for cellular physiology, and possible links between altered channel function and disease. Many cellular functions are directly or indirectly regulated by the free cytosolic calcium concentration. Thus, calcium levels must be very tightly regulated in time and space. Intracellular calcium ions are essential second messengers and play a role in many functions including, action potential generation, neurotransmitter and hormone release, muscle contraction, neurite outgrowth, synaptogenesis, calcium-dependent gene expression, synaptic plasticity and cell death. Calcium ions that control cell activity can be supplied to the cell cytosol from two major sources: the extracellular space or intracellular stores. Voltage-gated and ligand-gated channels are the primary way in which Ca(2+) ions enter from the extracellular space. The sarcoplasm reticulum (SR) in muscle and the endoplasmic reticulum in non-muscle cells are the main intracellular Ca(2+) stores: the ryanodine receptor (RyR) and inositol-triphosphate receptor channels are the major contributors of calcium release from internal stores.
MeSH term(s)	Animals ; Ataxia/genetics ; Calcium/chemistry ; Calcium Channels/genetics ; Calcium Channels, L-Type/metabolism ; Cytosol/metabolism ; Female ; Heterozygote ; Humans ; Ions ; Male ; Mice ; Mutation ; Night Blindness/genetics ; Sarcoplasmic Reticulum/metabolism
Chemical Substances	CACNA1F protein, human ; Calcium Channels ; Calcium Channels, L-Type ; Ions ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2008-05-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2262854-X
ISSN	1933-6969 ; 1933-6950
ISSN (online)	1933-6969
ISSN	1933-6950
DOI	10.4161/chan.2.3.5950
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Accessibility of targeted DHPR sites to streptavidin and functional effects of binding on EC coupling.

Lorenzon, Nancy M / Beam, Kurt G

The Journal of general physiology

2007 Volume 130, Issue 4, Page(s) 379–388

Abstract: In skeletal muscle, the dihydropyridine receptor (DHPR) in the plasma membrane (PM) serves as a Ca(2+) channel and as the voltage sensor for excitation-contraction (EC coupling), triggering Ca(2+) release via the type 1 ryanodine receptor (RyR1) in the ... ...

Abstract	In skeletal muscle, the dihydropyridine receptor (DHPR) in the plasma membrane (PM) serves as a Ca(2+) channel and as the voltage sensor for excitation-contraction (EC coupling), triggering Ca(2+) release via the type 1 ryanodine receptor (RyR1) in the sarcoplasmic reticulum (SR) membrane. In addition to being functionally linked, these two proteins are also structurally linked to one another, but the identity of these links remains unknown. As an approach to address this issue, we have expressed DHPR alpha(1S) or beta(1a) subunits, with a biotin acceptor domain fused to targeted sites, in myotubes null for the corresponding, endogenous DHPR subunit. After saponin permeabilization, the approximately 60-kD streptavidin molecule had access to the beta(1a) N and C termini and to the alpha(1S) N terminus and proximal II-III loop (residues 671-686). Steptavidin also had access to these sites after injection into living myotubes. However, sites of the alpha(1S) C terminus were either inaccessible or conditionally accessible in saponin- permeabilized myotubes, suggesting that these C-terminal regions may exist in conformations that are occluded by other proteins in PM/SR junction (e.g., RyR1). The binding of injected streptavidin to the beta(1a) N or C terminus, or to the alpha(1S) N terminus, had no effect on electrically evoked contractions. By contrast, binding of streptavidin to the proximal alpha(1S) II-III loop abolished such contractions, without affecting agonist-induced Ca(2+) release via RyR1. Moreover, the block of EC coupling did not appear to result from global distortion of the DHPR and supports the hypothesis that conformational changes of the alpha(1S) II-III loop are necessary for EC coupling in skeletal muscle.
MeSH term(s)	Animals ; Binding Sites ; Calcium Channels, L-Type/chemistry ; Calcium Channels, L-Type/metabolism ; Calcium Signaling ; Carrier Proteins/chemistry ; Carrier Proteins/metabolism ; Cells, Cultured ; Mice ; Muscle Contraction/physiology ; Muscle Fibers, Skeletal/metabolism ; Protein Binding ; Protein Interaction Mapping ; Protein Structure, Secondary ; Protein Subunits/metabolism ; Ryanodine Receptor Calcium Release Channel/metabolism ; Streptavidin/chemistry ; Streptavidin/metabolism ; Structure-Activity Relationship
Chemical Substances	Calcium Channels, L-Type ; Carrier Proteins ; Protein Subunits ; Ryanodine Receptor Calcium Release Channel ; biotin-binding proteins ; Streptavidin (9013-20-1)
Language	English
Publishing date	2007-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.200609730
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Monitoring performance degradation of cerebellar functions using computational neuroscience methods: implications on neurological diseases.

Nawrocki, Robert A / Shaalan, Majid / Shaheen, Sean E / Lorenzon, Nancy M

PloS one

2012 Volume 7, Issue 9, Page(s) e45581

Abstract: Neurodegeneration is a major cause of human disease. Within the cerebellum, neuronal degeneration and/or dysfunction has been associated with many diseases, including several forms of cerebellar ataxia, since normal cerebellar function is paramount for ... ...

Abstract	Neurodegeneration is a major cause of human disease. Within the cerebellum, neuronal degeneration and/or dysfunction has been associated with many diseases, including several forms of cerebellar ataxia, since normal cerebellar function is paramount for proper motor coordination, balance, and motor learning. The cerebellum represents a well-established neural circuit. Determining the effects of neuronal loss is of great importance for understanding the fundamental workings of the cerebellum and disease-associated dysfunctions. This paper presents computational modeling of cerebellar function in relation to neurodegeneration either affecting a specific cerebellar cell type, such as granule cells or Purkinje cells, or more generally affecting cerebellar cells and the implications on effects in relation to performance degradation throughout the progression of cell death. The results of the models show that the overall number of cells, as a percentage of the total cell number in the model, of a particular type and, primarily, their proximity to the circuit output, and not the neuronal convergence due to the relative number of cells of a particular type, is the main indicator of the gravity of the functional deficit caused by the degradation of that cell type. Specifically, the greater the percentage loss of neurons of a specific type and the closer proximity of those cells to the deep cerebellar neurons, the greater the deficit caused by the neuronal cell loss. These findings contribute to the understanding of the functional consequences of neurodegeneration and the functional importance of specific connectivity within a neuronal circuit.
MeSH term(s)	Cerebellum/cytology ; Cerebellum/physiology ; Cerebellum/physiopathology ; Computer Simulation ; Humans ; Models, Neurological ; Neurons/physiology
Language	English
Publishing date	2012-09-20
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0045581
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Bimolecular fluorescence complementation and targeted biotinylation provide insight into the topology of the skeletal muscle Ca ( 2+) channel β1a subunit.

Sheridan, David C / Moua, Ong / Lorenzon, Nancy M / Beam, Kurt G

Channels (Austin, Tex.)

2012 Volume 6, Issue 1, Page(s) 26–40

Abstract: In skeletal muscle, L-type calcium channels (DHPRs), localized to plasma membrane sarcoplasmic reticulum junctions, are tightly packed into groups of four termed tetrads. Here, we have used bimolecular fluorescence complementation (BiFC) and targeted ... ...

Abstract	In skeletal muscle, L-type calcium channels (DHPRs), localized to plasma membrane sarcoplasmic reticulum junctions, are tightly packed into groups of four termed tetrads. Here, we have used bimolecular fluorescence complementation (BiFC) and targeted biotinylation to probe the structure and organization of β1a subunits associated with native CaV 1.1 in DHPRs of myotubes. The construct YN-β1a-YC, in which the non-fluorescent fragments of YFP ("YN" corresponding to YFP residues 1-158, and "YC" corresponding to YFP residues 159-238) were fused, respectively, to the N- and C-termini of β1a, was fully functional and displayed yellow fluorescence within DHPR tetrads after expression in β1-knockout (β1KO) myotubes; this yellow fluorescence demonstrated the occurrence of BiFC of YN and YC on the β1a N- and C-termini. In these experiments, we avoided overexpression because control experiments in non-muscle cells indicated that this could result in non-specific BiFC. BiFC of YN-β1a-YC in DHPR tetrads appeared to be intramolecular between N- and C-termini of individual β1a subunits rather than between adjacent DHPRs because BiFC (1) was observed for YN-β1a-YC co-expressed with CaV 1.2 (which does not form tetrads) and (2) was not observed after co-expression of YN-β1a-YN plus YC-β1a-YC in β1KO myotubes. Thus, β1a function is compatible with N- and C-termini being close enough together to allow BiFC. However, both termini appeared to have positional freedom and not to be closely opposed by other junctional proteins since both were accessible to gold-streptavidin conjugates. Based on these results, a model is proposed for the arrangement of β1a subunits in DHPR tetrads.
MeSH term(s)	Animals ; Bacterial Proteins/genetics ; Biotin/genetics ; Biotinylation ; Calcium Channels, L-Type/physiology ; Cell Line ; Fluorescence ; Humans ; Luminescent Proteins/genetics ; Muscle Fibers, Skeletal/physiology ; Muscle, Skeletal/physiology ; Protein Subunits/physiology ; Transfection
Chemical Substances	Bacterial Proteins ; Calcium Channels, L-Type ; Luminescent Proteins ; Protein Subunits ; yellow fluorescent protein, Bacteria ; Biotin (6SO6U10H04)
Language	English
Publishing date	2012-01-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2262854-X
ISSN	1933-6969 ; 1933-6969
ISSN (online)	1933-6969
ISSN	1933-6969
DOI	10.4161/chan.18916
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Monitoring performance degradation of cerebellar functions using computational neuroscience methods

Robert A Nawrocki / Majid Shaalan / Sean E Shaheen / Nancy M Lorenzon

PLoS ONE, Vol 7, Iss 9, p e

implications on neurological diseases.

2012 Volume 45581

Abstract	Neurodegeneration is a major cause of human disease. Within the cerebellum, neuronal degeneration and/or dysfunction has been associated with many diseases, including several forms of cerebellar ataxia, since normal cerebellar function is paramount for proper motor coordination, balance, and motor learning. The cerebellum represents a well-established neural circuit. Determining the effects of neuronal loss is of great importance for understanding the fundamental workings of the cerebellum and disease-associated dysfunctions. This paper presents computational modeling of cerebellar function in relation to neurodegeneration either affecting a specific cerebellar cell type, such as granule cells or Purkinje cells, or more generally affecting cerebellar cells and the implications on effects in relation to performance degradation throughout the progression of cell death. The results of the models show that the overall number of cells, as a percentage of the total cell number in the model, of a particular type and, primarily, their proximity to the circuit output, and not the neuronal convergence due to the relative number of cells of a particular type, is the main indicator of the gravity of the functional deficit caused by the degradation of that cell type. Specifically, the greater the percentage loss of neurons of a specific type and the closer proximity of those cells to the deep cerebellar neurons, the greater the deficit caused by the neuronal cell loss. These findings contribute to the understanding of the functional consequences of neurodegeneration and the functional importance of specific connectivity within a neuronal circuit.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Metabolic biotinylation as a probe of supramolecular structure of the triad junction in skeletal muscle.

Lorenzon, Nancy M / Haarmann, Claudia S / Norris, Ethan E / Papadopoulos, Symeon / Beam, Kurt G

The Journal of biological chemistry

2004 Volume 279, Issue 42, Page(s) 44057–44064

Abstract: Excitation-contraction coupling in skeletal muscle involves conformational coupling between dihydropyridine receptors (DHPRs) in the plasma membrane and ryanodine receptors (RyRs) in the sarcoplasmic reticulum. However, it remains uncertain what regions, ...

Abstract	Excitation-contraction coupling in skeletal muscle involves conformational coupling between dihydropyridine receptors (DHPRs) in the plasma membrane and ryanodine receptors (RyRs) in the sarcoplasmic reticulum. However, it remains uncertain what regions, if any, of the two proteins interact with one another. Toward this end, it would be valuable to know the spatial interrelationships of DHPRs and RyRs within plasma membrane/sarcoplasmic reticulum junctions. Here we describe a new approach based on metabolic incorporation of biotin into targeted sites of the DHPR. To accomplish this, cDNAs were constructed with a biotin acceptor domain (BAD) fused to selected sites of the DHPR, with fluorescent protein (XFP) attached at a second site. All of the BAD-tagged constructs properly targeted to junctions (as indicted by small puncta of XFP) and were functional for excitation-contraction coupling. To determine whether the introduced BAD was biotinylated and accessible to avidin (approximately 60 kDa), myotubes were fixed, permeablized, and exposed to fluorescently labeled avidin. Upon expression in beta1-null or dysgenic (alpha1S-null) myotubes, punctate avidin fluorescence co-localized with the XFP puncta for BAD attached to the beta1a N- or C-terminals, or the alpha1S N-terminal or II-III loop. However, BAD fused to the alpha1S C-terminal was inaccessible to avidin in dysgenic myotubes (containing RyR1). In contrast, this site was accessible to avidin when the identical construct was expressed in dyspedic myotubes lacking RyR1. These results indicate that avidin has access to a number of sites of the DHPR within fully assembled (RyR1-containing) junctions, but not to the alpha1S C-terminal, which appears to be occluded by the presence of RyR1.
MeSH term(s)	Amino Acid Sequence ; Animals ; Bacterial Proteins/analysis ; Biotinylation ; Calcium Channels, L-Type/chemistry ; Calcium Channels, L-Type/physiology ; Cell Membrane/physiology ; Luminescent Proteins/analysis ; Molecular Sequence Data ; Muscle, Skeletal/physiology ; Polymerase Chain Reaction ; Recombinant Fusion Proteins/chemistry ; Ryanodine Receptor Calcium Release Channel/chemistry ; Ryanodine Receptor Calcium Release Channel/physiology ; Sarcoplasmic Reticulum/physiology
Chemical Substances	Bacterial Proteins ; Calcium Channels, L-Type ; Luminescent Proteins ; Recombinant Fusion Proteins ; Ryanodine Receptor Calcium Release Channel ; yellow fluorescent protein, Bacteria
Language	English
Publishing date	2004-07-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M405318200
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Three-dimensional localization of the α and β subunits and of the II-III loop in the skeletal muscle L-type Ca2+ channel.

Szpyt, John / Lorenzon, Nancy / Perez, Claudio F / Norris, Ethan / Allen, Paul D / Beam, Kurt G / Samsó, Montserrat

The Journal of biological chemistry

2012 Volume 287, Issue 52, Page(s) 43853–43861

Abstract: The L-type Ca(2+) channel (dihydropyridine receptor (DHPR) in skeletal muscle acts as the voltage sensor for excitation-contraction coupling. To better resolve the spatial organization of the DHPR subunits (α(1s) or Ca(V)1.1, α(2), β(1a), δ1, and γ), we ... ...

Abstract	The L-type Ca(2+) channel (dihydropyridine receptor (DHPR) in skeletal muscle acts as the voltage sensor for excitation-contraction coupling. To better resolve the spatial organization of the DHPR subunits (α(1s) or Ca(V)1.1, α(2), β(1a), δ1, and γ), we created transgenic mice expressing a recombinant β(1a) subunit with YFP and a biotin acceptor domain attached to its N- and C- termini, respectively. DHPR complexes were purified from skeletal muscle, negatively stained, imaged by electron microscopy, and subjected to single-particle image analysis. The resulting 19.1-Å resolution, three-dimensional reconstruction shows a main body of 17 × 11 × 8 nm with five corners along its perimeter. Two protrusions emerge from either face of the main body: the larger one attributed to the α(2)-δ1 subunit that forms a flexible hook-shaped feature and a smaller protrusion on the opposite side that corresponds to the II-III loop of Ca(V)1.1 as revealed by antibody labeling. Novel features discernible in the electron density accommodate the atomic coordinates of a voltage-gated sodium channel and of the β subunit in a single docking possibility that defines the α1-β interaction. The β subunit appears more closely associated to the membrane than expected, which may better account for both its role in localizing the α(1s) subunit to the membrane and its suggested role in excitation-contraction coupling.
MeSH term(s)	Animals ; Calcium Channels, L-Type/genetics ; Calcium Channels, L-Type/metabolism ; Calcium Channels, L-Type/ultrastructure ; Humans ; Mice ; Mice, Transgenic ; Microscopy, Electron ; Molecular Docking Simulation ; Muscle Proteins/genetics ; Muscle Proteins/metabolism ; Muscle Proteins/ultrastructure ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/ultrastructure ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Protein Subunits
Chemical Substances	Calcium Channels, L-Type ; Muscle Proteins ; Protein Subunits
Language	English
Publishing date	2012-11-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M112.419283
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Disease causing mutations of calcium channels.

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Article: Accessibility of targeted DHPR sites to streptavidin and functional effects of binding on EC coupling.

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Article ; Online: Monitoring performance degradation of cerebellar functions using computational neuroscience methods: implications on neurological diseases.

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Article ; Online: Bimolecular fluorescence complementation and targeted biotinylation provide insight into the topology of the skeletal muscle Ca ( 2+) channel β1a subunit.

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Article ; Online: Monitoring performance degradation of cerebellar functions using computational neuroscience methods

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Article: Metabolic biotinylation as a probe of supramolecular structure of the triad junction in skeletal muscle.

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Article ; Online: Three-dimensional localization of the α and β subunits and of the II-III loop in the skeletal muscle L-type Ca2+ channel.

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