CACNB2: An Emerging Pharmacological Target for Hypertension, Heart Failure, Arrhythmia and Mental Disorders.

The voltage-gated Cav1.2 calcium channels respond to membrane depolarization by increasing the membrane permeability to Ca(2+), a major signal for cardiac muscle contraction, regulation of vascular tone and CREB-dependent transcriptional activation. CACNB2 is one of the four homologous genes coding for the auxiliary Cavβ subunits, which are important modulators of the Ca(2+) channel activity.

Cav1.2, cell proliferation, and new target in atherosclerosis.

Cav1.2 calcium channels are the principal proteins involved in electrical, mechanical, and/or signaling functions of the cell. Cav1.

Selective fluorophore-assisted light inactivation of voltage-gated calcium channels.

Fluorophore-assisted light inactivation (FALI) is an investigative tool to inactivate fluorescently labeled proteins by a mechanism of in situ photodestruction. We found that Ca(v)1.2 (L-type) and Ca(v)3.

CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease.

One of the most consistent genetic findings to have emerged from bipolar disorder genome wide association studies (GWAS) is with CACNA1C, a gene that codes for the α(1C) subunit of the Ca(v)1.2 voltage-dependent L-type calcium channel (LTCC). Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders, as well as changes in brain function and structure in control subjects who have no diagnosable psychiatric illness.

Molecular Determinants of Cav1.2 Calcium Channel Inactivation.

Voltage-gated L-type Cav1.2 calcium channels couple membrane depolarization to transient increase in cytoplasmic free Ca(2+) concentration that initiates a number of essential cellular functions including cardiac and vascular muscle contraction, gene expression, neuronal plasticity, and exocytosis. Inactivation or spontaneous termination of the calcium current through Cav1.

Microdomain organization and frequency-dependence of CREB-dependent transcriptional signaling in heart cells.

Voltage-gated Ca(v)1.2 calcium channels couple membrane depolarization to cAMP response-element-binding protein (CREB)-dependent transcriptional activation. To investigate the spatial and temporal organization of CREB-dependent transcriptional nuclear microdomains, we combined perforated patch-clamp technique and FRET microscopy for monitoring CREB and CREB-binding protein interaction in the nuclei of live cells.

Cardiac phenotype induced by a dysfunctional α 1C transgene: a general problem for the transgenic approach.

Based on stable integration of recombinant DNA into a host genome, transgenic technology has become an important genetic engineering methodology. An organism whose genetic characteristics have been altered by the insertion of foreign DNA is supposed to exhibit a new phenotype associated with the function of the transgene. However, successful insertion may not be sufficient to achieve specific modification of function.

Oligomerization of Cavbeta subunits is an essential correlate of Ca2+ channel activity.

Voltage-gated calcium channels conduct Ca(2+) ions in response to membrane depolarization. The resulting transient increase in cytoplasmic free calcium concentration is a critical trigger for the initiation of such vital responses as muscle contraction and transcription. L-type Ca(v)1.

Molecular remodeling of ion channels, exchangers and pumps in atrial and ventricular myocytes in ischemic cardiomyopathy.

Existing molecular knowledge base of cardiovascular diseases is rudimentary because of lack of specific attribution to cell type and function. The aim of this study was to investigate cell-specific molecular remodeling in human atrial and ventricular myocytes associated with ischemic cardiomyopathy. Our strategy combines two technological innovations, laser-capture microdissection of identified cardiac cells in selected anatomical regions of the heart and splice microarray of a narrow catalog of the functionally most important genes regulating ion homeostasis.

Effect of Ca(v)beta subunits on structural organization of Ca(v)1.2 calcium channels.

Background: Voltage-gated Ca(v)1.2 calcium channels play a crucial role in Ca(2+) signaling. The pore-forming alpha(1C) subunit is regulated by accessory Ca(v)beta subunits, cytoplasmic proteins of various size encoded by four different genes (Ca(v)beta(1)-beta(4)) and expressed in a tissue-specific manner.

Functional properties of the CaV1.2 calcium channel activated by calmodulin in the absence of alpha2delta subunits.

Voltage-activated CaV1.2 calcium channels require association of the pore-forming alpha1C subunit with accessory CaVbeta and alpha2delta subunits. Binding of a single calmodulin (CaM) to alpha1C supports Ca2+-dependent inactivation (CDI).

Principles of calcium signaling. Salisbury Cove, Maine, June 28-30, 2007.

A three-day International Symposium entitled "Principles of Calcium Signaling" organized by James N. Weiss, Yale E. Goldman, Stéphane Hatem, Lars Cleemann and Nikolai M.

Calmodulin-dependent gating of Ca(v)1.2 calcium channels in the absence of Ca(v)beta subunits.

It is generally accepted that to generate calcium currents in response to depolarization, Ca(v)1.2 calcium channels require association of the pore-forming alpha(1C) subunit with accessory Ca(v)beta and alpha(2)delta subunits. A single calmodulin (CaM) molecule is tethered to the C-terminal alpha(1C)-LA/IQ region and mediates Ca2+-dependent inactivation of the channel.

New Determinant for the CaVbeta2 subunit modulation of the CaV1.2 calcium channel.

Ca(v)beta subunits support voltage gating of Ca(v)1.2 calcium channels and play important role in excitation-contraction coupling. The common central membrane-associated guanylate kinase (MAGUK) region of Ca(v)beta binds to the alpha-interaction domain (AID) and the IQ motif of the pore-forming alpha(1C) subunit, but these two interactions do not explain why the cardiac Ca(v)beta(2) subunit splice variants differentially modulate inactivation of Ca(2+) currents (I(Ca)).

Analysis of functional signaling domains from fluorescence imaging and the two-dimensional continuous wavelet transform.

A technique that utilizes the one-dimensional (1D) continuous wavelet transform (CWT) of linearized fluorescence resonance energy transfer (FRET) microscopic images has been extended to identify signaling macro- and microdomains in cell plasma membranes by incorporating the two-dimensional (2D) CWT of time-lapse fluorescence and/or FRET images. Signaling domains were identified from differences in wavelet coefficient matrices, and there was good agreement between the 1D and 2D methods on examining a), static fluorescent images of COS1 cells expressing calmodulin kinase II fused with enhanced yellow fluorescent protein, and b), time lapse FRET images of reporters of protein kinase C (PKC) (PKC activity reporter) and adenylyl cyclase dynamics (cAMP) activity within COS1 plasma membrane confines after stimulation by phorbol-12,13-dibutyrate or forskolin, respectively. The proposed 2D wavelet-based image analysis effectively detected phosphorylation/dephosphorylation signaling microdomains (PKC) as well as those reflective of cAMP without the limitation of requiring linearized signals imposed by the 1D approach.

Atherosclerosis-related molecular alteration of the human CaV1.2 calcium channel alpha1C subunit.

Atherosclerosis is an inflammatory process characterized by proliferation and dedifferentiation of vascular smooth muscle cells (VSMC). Ca(v)1.2 calcium channels may have a role in atherosclerosis because they are essential for Ca(2+)-signal transduction in VSMC.

Activation of protein kinase C augments T-type Ca2+ channel activity without changing channel surface density.

T-type Ca2+ channels play essential roles in numerous cellular processes. Recently, we reported that phorbol-12-myristate-13-acetate (PMA) potently enhanced the current amplitude of Cav3.2 T-type channels reconstituted in Xenopus oocytes.

Molecular rearrangements of the Kv2.1 potassium channel termini associated with voltage gating.

The voltage-gated Kv2.1 channel is composed of four identical subunits folded around the central pore and does not inactivate appreciably during short depolarizing pulses. To study voltage-induced relative molecular rearrangements of the channel, Kv2.

Calcium channel inactivation: possible role in signal transduction and Ca2+ signaling.

Voltage gated Ca2+ channels are major routes for the entry of intracellular Ca2+ coupled to membrane depolarization that appear to vary greatly with respect to their voltage dependence and kinetics. Such variability maybe in part related to the attached signaling properties of the channel, in addition to the transport of calcium. In the present review we consider the possible role of calcium-dependent inactivation of Cav1.

Identification of plasma membrane macro- and microdomains from wavelet analysis of FRET microscopy.

In this study, we sought to characterize functional signaling domains by applying the multiresolution properties of the continuous wavelet transform to fluorescence resonance energy transfer (FRET) microscopic images of plasma membranes. A genetically encoded FRET reporter of protein kinase C (PKC)-dependent phosphorylation was expressed in COS1 cells. Differences between wavelet coefficient matrices revealed several heterogeneous domains (typically ranging from 1 to 5 microm), reflecting the dynamic balance between PKC and phosphatase activity during stimulation with phorbol-12,13-dibutyrate or acetylcholine.

Differential role of the alpha1C subunit tails in regulation of the Cav1.2 channel by membrane potential, beta subunits, and Ca2+ ions.

Voltage-gated Ca(v)1.2 channels are composed of the pore-forming alpha1C and auxiliary beta and alpha2delta subunits. Voltage-dependent conformational rearrangements of the alpha1C subunit C-tail have been implicated in Ca2+ signal transduction.

New short splice variants of the human cardiac Cavbeta2 subunit: redefining the major functional motifs implemented in modulation of the Cav1.2 channel.

Two new short splice variants of the Ca2+ channel beta2 subunit were cloned from human heart poly(A)(+) mRNA. The 410-amino acid beta2f subunit is encoded by exons 1A, 2A, 3, 4, 12, 13, and 14 of the human Cavbeta2 gene and lacks the protein kinase A phosphorylation site, the beta-interaction domain (De Waard, M., Pragnell, M.

Voltage-gated rearrangements associated with differential beta-subunit modulation of the L-type Ca(2+) channel inactivation.

Auxiliary beta-subunits bound to the cytoplasmic alpha(1)-interaction domain of the pore-forming alpha(1C)-subunit are important modulators of voltage-gated Ca(2+) channels. The underlying mechanisms are not yet well understood. We investigated correlations between differential modulation of inactivation by beta(1a)- and beta(2)- subunits and structural responses of the channel to transition into distinct functional states.