L-type calcium channel auto-regulation of transcription

doi:10.1016/j.ceca.2011.01.001

Cell Calcium

Volume 49, Issue 5, May 2011, Pages 306-313

https://doi.org/10.1016/j.ceca.2011.01.001 Get rights and content

Abstract

L-type calcium channels (LTCC) impact the function of nearly all excitable cells. The classical LTCC function is to mediate trans-sarcolemmal Ca²⁺ flux. This review focuses on the contribution of a mobile segment of the LTCC that regulates ion channel function, and also serves as a regulator of transcription in the nucleus. Specifically we highlight recent work demonstrating an auto-feedback regulatory pathway whereby the LTCC transcription factor regulates the LTCC. Also discussed is acute and long-term regulation of function by the LTCC-transcription regulator.

Introduction

L-type calcium channels (LTCC) couple membrane depolarization to cytosolic calcium entry. In turn, calcium bridges excitation to contraction in cardiac myocytes. Cytosolic Ca²⁺-entry via LTCC stimulates a larger release of Ca²⁺ from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyR₂). Details of this process are the topic of excellent reviews [1], [2]. A second, less-appreciated contribution of Ca²⁺ in cardiac myocytes is to couple excitation to transcription. The goal of this review is to introduce a relatively new role for cardiac L-type calcium channels (LTCC) – a direct signal transduction pathway linking LTCC function to transcriptional regulation. The focus of this review is mainly on cardiac LTCC, but there are broader implications given that LTCC are expressed across a wide-range of tissue types [3].

The heart adapts to changing demands by matching output. This occurs on a broad range of time scales from acute beat-to-beat changes to long-term growth related changes. Acute sympathetic nervous stimulation causes a positive inotropism on a relatively rapid time scale. On a considerably longer time scale the growth of the heart during maturation is matched to its functional load [4]. Similarly, exercise or pregnancy stimulates heart growth [5] resulting in a physiological and reversible hypertrophy. Numerous signaling cascades are implicated in the regulation of heart growth including, but not limited to Ca²⁺-regulated processes [6]. Heart growth is defined here as a change in heart size, principally cardiomyocyte cell size. The detail of size alterations depend on the specific stimuli [7]. Pathological stimuli also promote heart growth, though the signaling pathways are distinct from growth stimulated by physiological cues [8]. Central to this review, cytosolic Ca²⁺ is a key contributor to a number of signaling systems. Ca²⁺-activated calcineurin (CaN), and calcium–calmodulin dependent kinase (CaMKII) are two examples of Ca²⁺-effectors in cardiomyocyte adaptive signaling. Alterations in cytosolic Ca²⁺-entry are upstream of these signaling cascades, and thus represent a potentially sensitive target for regulation of this diverse signaling. In this review we summarize findings that are consistent with LTCC sensing changes in Ca²⁺-entry, and then coupling such changes to reflexive adjustments in LTCC expression via a mobile segment derived from the LTCC.

Section snippets

LTCC structure

LTCC exists as part of a multi-protein complex in cardiomyocytes [9]. The main pore-forming subunit of the LTCC in the myocardium is Ca_V1.2. Ca_V1.2 is also expressed in vascular smooth muscle, pancreatic β-cells, neurons, and developing skeletal muscle. Closely related Ca_V1.1 is expressed in mature skeletal muscle. Ca_V1.3 is expressed in atrial myocytes, neurons, and chromaffin cells. Ca_V1.4 channels, largely expressed in retina complete the Ca_V1 family. This review focuses mainly on the Ca_V1.2

L-type calcium channel (cacna1c) promoter

Ca_V1.2 is encoded by the cacna1c gene which is located on chromosome 6 in mouse and 12 in human. By all accounts it is a very complex locus. Databases list as many as 35 isoforms. In human there are 7 predicted alternative promoters with variations in the mRNA including 5′ and 3′ truncations [26]. Ca_V1.2 expression has been shown to be regulated by β-adrenergic stimulation [27], [28], α adrenergic stimulation [27], [28], [29], androgens [30], [31], elevated blood pressure [32], atrial

DCT in the nucleus regulates transcription

LTCC couples membrane depolarization to gene expression [50]. Several mechanisms have been proposed to explain excitation–transcription coupling: (1) signaling by Ca²⁺ secondary to LTCC-mediated cytosolic Ca²⁺-entry; (2) signaling by CaM/CaMKII; and (3) signaling by DCT.

(1)
LTCC activity is linked to transcriptional regulation of a variety of genes such as c-fos in hypoxia [51], RhoA/Rok, myocardin, and SRF pathways in smooth muscle [52], and in cardiac memory [53]. Cardiac memory describes

DCT signaling of cardiac myocyte growth

There is overwhelming evidence that LTCC pharmacological blockade reduces cardiac mass in patients. Animal studies suggest that LTCC pharmacological blockade can be mediated by direct myocardial actions, rather than activity secondary to relief of hypertension. In mice LTCC-mediated Ca²⁺ entry is a proximal signal for cardiac hypertrophy [71], and subpressor doses of nifedipine inhibit cardiac hypertrophy induced experimentally by pressure overload via aortic constriction [72]. LTCC blockade

LTCC, DCT, and acute feedback regulation by Ca²⁺

The unambiguous contribution of LTCC to function is to permit cytosolic Ca²⁺-entry. Depolarization opens LTCC, Ca²⁺-entry occurs, and LTCC inactivation commences. Two major mechanisms limit Ca²⁺-entry: voltage-dependent inactivation (VDI), and Ca²⁺-dependent inactivation (CDI) [74]. VDI may dominate in basal state, whereas CDI becomes a dominate mechanism following β-adrenergic stimulation [75]. CDI occurs when Ca permeating via the LTCC interacts with CaM that is pre-bound to the LTCC.

Modulation of LTCC Involves DCT

I_Ca,L via LTCC triggers a greater ryanodine receptor-based Ca²⁺ release in cardiomyocytes. Thus subtle changes in LTCC function lead to greater downstream changes. Sympathetic stimulation of cardiomyocytes causes activation of the β-adrenergic signaling axis, ultimately increasing protein kinase A (PKA) activity. LTCC are a key substrate for β-adrenergic activated protein kinase A. Thus, a critical element of understanding the β-adrenergic signaling axis is a more detailed understanding of LTCC

Perspective

LTCC Ca²⁺-entry regulates numerous effector pathways that ultimately regulate transcription. In turn, LTCC are regulated by a variety of physiological and pathophysiological stimuli. DCT represents a possible privileged signaling pathway between functioning LTCC and the nucleus. A major question that needs attention is the relative importance of DCT among LTCC-dependent signaling cascades. Further complexity, or perhaps opportunities, for signal transduction crosstalk may arise from the known

Acknowledgements

We are grateful for the many insightful discussions with Dr Douglas Andres. This work was supported by NIH HL074091 (JS), and an NIH Interdisciplinary Cardiovascular Sciences Training Grant HL-072734 (SMC).

References (86)

K.M. Dibb et al.
Analysis of cellular calcium fluxes in cardiac muscle to understand calcium homeostasis in the heart
Cell Calcium
(2007)
R.M. Case et al.
Evolution of calcium homeostasis: from birth of the first cell to an omnipresent signalling system
Cell Calcium
(2007)
R.D. Zuhlke et al.
Ca²⁺-sensitive inactivation and facilitation of L-type Ca²⁺ channels both depend on specific amino acid residues in a consensus calmodulin-binding motif in the(alpha)1C subunit
J. Biol. Chem.
(2000)
P. Pate et al.
Determinants for calmodulin binding on voltage-dependent Ca²⁺ channels
J. Biol. Chem.
(2000)
J. Mouton et al.
Interactions of calmodulin with two peptides derived from the C-terminal cytoplasmic domain of the Cav1.2 Ca²⁺ channel provide evidence for a molecular switch involved in Ca²⁺-induced inactivation
J. Biol. Chem.
(2001)
B.L. Gerhardstein et al.
Proteolytic Processing of the C Terminus of the alpha 1C subunit of L-type calcium channels and the role of a proline-rich domain in membrane tethering of proteolytic fragments
J. Biol. Chem.
(2000)
I.Q. Fan et al.
Transcriptional regulation of L-type calcium channel expression in cardiac myocytes
J. Mol. Cell. Cardiol.
(2000)
X.Z. Shi et al.
Negative transcriptional regulation of human colonic smooth muscle Cav1.2 channels by p50 and p65 subunits of nuclear factor-kappaB
Gastroenterology
(2005)
A.J. Davidoff et al.
Expression of calcium channels in adult cardiac myocytes is regulated by calcium
J. Mol. Cell. Cardiol.
(1997)
L. Pang et al.
Tissue-specific expression of two human Ca(v)1.2 isoforms under the control of distinct 5′ flanking regulatory elements
FEBS Lett.
(2003)

N.I. Saada et al.

Expression of multiple CaV1.2 transcripts in rat tissues mediated by different promoters

Cell Calcium

(2005)

Y. Blumenstein et al.

A novel long N-terminal isoform of human L-type Ca²⁺ channel is up-regulated by protein kinase C

J. Biol. Chem.

(2002)

B. Dai et al.

A new promoter for alpha1C subunit of human L-type cardiac calcium channel Ca(V)1.2

Biochem. Biophys. Res. Commun.

(2002)

N.M. Soldatov et al.

Molecular structures involved in L-type calcium channel inactivation. Role of the carboxyl-terminal region encoded by exons 40–42 in alpha1C subunit in the kinetics and Ca²⁺ dependence of inactivation

J. Biol. Chem.

(1997)

N.M. Soldatov et al.

Different voltage-dependent inhibition by dihydropyridines of human Ca²⁺ channel splice variants

J. Biol. Chem.

(1995)

T.H. Murphy et al.

L-type voltage-sensitive calcium channels mediate synaptic activation of immediate early genes

Neuron

(1991)

K. Deisseroth et al.

Signaling from synapse to nucleus: the logic behind the mechanisms

Curr. Opin. Neurobiol.

(2003)

E. Kobrinsky et al.

Voltage-gated mobility of the Ca²⁺ channel cytoplasmic tails and its regulatory role

J. Biol. Chem.

(2003)

N. Gomez-Ospina et al.

The C terminus of the L-type voltage-gated calcium channel ca(v)1.2 encodes a transcription factor

Cell

(2006)

H. Liang et al.

Unified mechanisms of Ca²⁺ regulation across the Ca²⁺ channel family

Neuron

(2003)

M.G. Erickson et al.

Preassociation of calmodulin with voltage-gated Ca(2+) channels revealed by FRET in single living cells

Neuron

(2001)

E. Kobrinsky et al.

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

J. Biol. Chem.

(2005)

T. Lemke et al.

Unchanged beta-adrenergic stimulation of cardiac L-type calcium channels in Ca v 1.2 phosphorylation site S1928A mutant mice

J. Biol. Chem.

(2008)

T. Gao et al.

cAMP-dependent regulation of cardiac L-type Ca²⁺ channels requires membrane targeting of PKA and phosphorylation of channel subunits

Neuron

(1997)

D.M. Bers

Calcium cycling and signaling in cardiac myocytes

Annu. Rev. Physiol.

(2008)

R. Zak

Growth of the Heart in Health and Disease

(1984)

B.C. Bernardo, K.L. Weeks, L. Pretorius, J.R. McMullen, Molecular distinction between physiological and pathological...

J.D. Molkentin

Dichotomy of Ca²⁺ in the heart: contraction versus intracellular signaling

J. Clin. Invest.

(2006)

G.W. Dorn et al.

Phenotyping hypertrophy: eschew obfuscation

Circ. Res.

(2003)

J.A. Hill et al.

Cardiac plasticity

N. Engl. J. Med.

(2008)

S. Dai et al.

Supramolecular assemblies and localized regulation of voltage-gated ion channels

Physiol. Rev.

(2009)

L. Yang, A. Katchman, J.P. Morrow, D. Doshi, S.O. Marx, Cardiac L-type calcium channel (Cav1.2) associates with {gamma}...

B. Hille

Ion Channels of Excitable Membranes

(2001)

J.T. Hulme et al.

Sites of proteolytic processing and noncovalent association of the distal C-terminal domain of CaV1.1 channels in skeletal muscle

Proc. Natl. Acad. Sci. U.S.A.

(2005)

G.S. Pitt et al.

Molecular basis of CaM tethering and Ca{super2+}-dependent inactivation of L-type Ca{super2+} channels

J. Biol. Chem.

(2001)

E.Y. Kim, C.H. Rumpf, F. Van Petegem, R.J. Arant, F. Findeisen, E.S. Cooley, E.Y. Isacoff, D.L. Minor Jr., Multiple...

J.L. Fallon et al.

Crystal structure of dimeric cardiac L-type calcium channel regulatory domains bridged by Ca²⁺ calmodulins

Proc. Natl. Acad. Sci. U.S.A.

(2009)

Y. Wu et al.

Calmodulin kinase and a calmodulin-binding ‘IQ’ domain facilitate L-type Ca²⁺ current in rabbit ventricular myocytes by a common mechanism

J. Physiol.

(2001)

A. Hudmon et al.

CaMKII tethers to L-type Ca²⁺ channels, establishing a local and dedicated integrator of Ca²⁺ signals for facilitation

J. Cell. Biol.

(2005)

C. Pang, S.M. Crump, L. Jin, R.N. Correll, B.S. Finlin, J. Satin, D.A. Andres, Rem GTPase interacts with the proximal...

C.S. Muller, A. Haupt, W. Bildl, J. Schindler, H.G. Knaus, M. Meissner, B. Rammner, J. Striessnig, V. Flockerzi, B....

K.S. De Jongh et al.

Differential proteolysis of the full-length form of the L-type calcium channel alpha 1 subunit by calpain

J. Neurochem.

(1994)

E. Schroder et al.

L-type calcium channel C terminus autoregulates transcription

Circ. Res.

(2009)

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Essential to beat-to-beat heart function is the ability for cardiomyocytes to propagate electrical excitation and generate contractile force. Both excitation and contractility depend on specific ventricular ion channels, which include the L-type calcium channel (LTCC) and the connexin 43 (Cx43) gap junction. Each of these two channels is localized to a distinct subdomain of the cardiomyocyte plasma membrane. In this review, we focus on regulatory mechanisms that govern the lifecycles of LTCC and Cx43, from their biogenesis in the nucleus to directed delivery to T-tubules and intercalated discs, respectively. We discuss recent findings on how alternative promoter usage, tissue-specific transcription, and alternative splicing determine precise ion channel expression levels within a cardiomyocyte. Moreover, recent work on microtubule and actin-dependent trafficking for Cx43 and LTCC are introduced. Lastly, we discuss how human cardiac disease phenotypes can be attributed to defects in distinct mechanisms of channel regulation at the level of gene expression and channel trafficking. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.
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The dCT fragment corresponds to the fragment spanning from the consensus calpain cleavage site to the C-terminal end of the Cav1.2 channel protein (α subunit). Like other α subunit C-terminal fragments, the dCT fragment was originally associated with the regulation of channel gating (20, 21). The first clue of a nuclear role for the dCT fragment came with the observation of its nuclear presence in neurons (22) and, more recently, in cardiomyocytes (21).
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Reviews addressing specific related topics include those on synaptic transmission (Meir et al., 1999; Neher and Sakaba, 2008), T-type currents (Perez-Reyes, 2003; Cueni et al., 2009), calcium-dependent inactivation in neurons (Budde et al., 2002), dynamics of calcium signaling in neurons (Augustine et al., 2003), models of calcium sparks and waves (Coombes et al., 2004), L-type currents in the heart (Bodi et al., 2005), the role of calcium currents in circadian rhythms (Brown and Piggins, 2007), calcium release and the roles of ryanodine receptors in heart and skeletal muscle diseases (Zalk et al., 2007), Ca2+ channels in chromaffin cells (Marcantoni et al., 2008) and calcium dynamics in relation to absence epilepsy (Weiergräber et al., 2010). Calcium ion influx through L-type channels leads via various signaling pathways to the activation of transcription factors such as CREB and hence the expression of genes that are essential for synaptic plasticity and other important cellular processes (Dolmetsch et al., 2001; Hardingham et al., 2001; Mori et al., 2004; Power and Sah, 2005; Satin et al., 2011). For example, it is known that activation of L-type Ca2+ channels increases the expression of certain genes required for the survival of hippocampal CA1 neurons after ischemic events in the forebrain (Li et al., 2007b).
Ca²⁺ currents in neurons and muscle cells have been classified as being one of 5 types, of which four, L, N, P/Q and R were said to be high threshold and one, T, was designated low threshold. This review focuses on quantitative aspects of L-type currents. L-type channels are now distinguished according to their structure as one of four main subtypes Ca_v1.1–Ca_v1.4. L-type calcium currents play many fundamental roles in cellular dynamical processes including control of firing rate and pacemaking in neurons and cardiac cells, the activation of transcription factors involved in synaptic plasticity and in immune cells. The half-activation potentials of L-type currents (I_CaL) have been ascribed values as low as −50 mV and as high as near 0 mV. The inactivation of I_CaL has been found to be both voltage (VDI) and calcium-dependent (CDI) and the latter component may involve calcium-induced calcium release. CDI is often an important aspect of dynamical models of cell electrophysiology. We describe the basic components in modeling I_CaL including activation and both voltage and calcium dependent inactivation and the two main approaches to determining the current. We review, by means of tables of values from over 65 representative studies, the various details of the dynamical properties associated with I_CaL that have been found experimentally or employed in the last 25 years in deterministic modeling in various nervous system and cardiac cells. Distributions and statistics of several parameters related to activation and inactivation are obtained. There are few reliable complete experimental data on L-type calcium current kinetics for cells at physiological calcium ion concentrations. Neurons are divided approximately into two groups with experimental half-activation potentials that are high, ≈ −18.3 mV, or low, ≈ −36.4 mV, which correspond closely with those for Ca_v1.2 and Ca_v1.3 channels in physiological solutions. There are very few complete experimental data on time constants of activation, those available suggesting values around 0.5–2 ms. In modeling, a wide range of time constants has been employed. A major problem for quantitative studies due to lack of experimental data has been the use of kinetic parameters from one cell type for others. Inactivation time constants for VDI have been found experimentally with average 65 ms. Examples of calculations of I_CaL are made for linear and constant field methods and the effects of CDI are illustrated for single and double pulse protocols and the results compared with experiment. The review ends with a discussion and analysis of experimental subtype (Ca_v1.1–Ca_v1.4) properties and their roles in normal, including pacemaker, activity, and many pathological states.

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ReviewL-type calcium channel auto-regulation of transcription

Abstract

Introduction

Section snippets

LTCC structure

L-type calcium channel (cacna1c) promoter

DCT in the nucleus regulates transcription

DCT signaling of cardiac myocyte growth

LTCC, DCT, and acute feedback regulation by Ca2+

Modulation of LTCC Involves DCT

Perspective

Acknowledgements

Cell Calcium

Cell Calcium

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Mol. Cell. Cardiol.

Gastroenterology

J. Mol. Cell. Cardiol.

FEBS Lett.

Cell Calcium

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Neuron

Curr. Opin. Neurobiol.

J. Biol. Chem.

Cell

Neuron

Neuron

J. Biol. Chem.

J. Biol. Chem.

Neuron

Calcium cycling and signaling in cardiac myocytes

Annu. Rev. Physiol.

Growth of the Heart in Health and Disease

Dichotomy of Ca2+ in the heart: contraction versus intracellular signaling

J. Clin. Invest.

Phenotyping hypertrophy: eschew obfuscation

Circ. Res.

Cardiac plasticity

N. Engl. J. Med.

Supramolecular assemblies and localized regulation of voltage-gated ion channels

Physiol. Rev.

Ion Channels of Excitable Membranes

Sites of proteolytic processing and noncovalent association of the distal C-terminal domain of CaV1.1 channels in skeletal muscle

Proc. Natl. Acad. Sci. U.S.A.

Molecular basis of CaM tethering and Ca{super2+}-dependent inactivation of L-type Ca{super2+} channels

J. Biol. Chem.

Crystal structure of dimeric cardiac L-type calcium channel regulatory domains bridged by Ca2+ calmodulins

Proc. Natl. Acad. Sci. U.S.A.

Calmodulin kinase and a calmodulin-binding ‘IQ’ domain facilitate L-type Ca2+ current in rabbit ventricular myocytes by a common mechanism

J. Physiol.

CaMKII tethers to L-type Ca2+ channels, establishing a local and dedicated integrator of Ca2+ signals for facilitation

J. Cell. Biol.

Differential proteolysis of the full-length form of the L-type calcium channel alpha 1 subunit by calpain

J. Neurochem.

L-type calcium channel C terminus autoregulates transcription

Circ. Res.

Review
L-type calcium channel auto-regulation of transcription

LTCC, DCT, and acute feedback regulation by Ca²⁺

Dichotomy of Ca²⁺ in the heart: contraction versus intracellular signaling

Crystal structure of dimeric cardiac L-type calcium channel regulatory domains bridged by Ca²⁺ calmodulins

Calmodulin kinase and a calmodulin-binding ‘IQ’ domain facilitate L-type Ca²⁺ current in rabbit ventricular myocytes by a common mechanism

CaMKII tethers to L-type Ca²⁺ channels, establishing a local and dedicated integrator of Ca²⁺ signals for facilitation