ReviewL-type calcium channel auto-regulation of transcription
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 CaV1.2. CaV1.2 is also expressed in vascular smooth muscle, pancreatic β-cells, neurons, and developing skeletal muscle. Closely related CaV1.1 is expressed in mature skeletal muscle. CaV1.3 is expressed in atrial myocytes, neurons, and chromaffin cells. CaV1.4 channels, largely expressed in retina complete the CaV1 family. This review focuses mainly on the CaV1.2
L-type calcium channel (cacna1c) promoter
CaV1.2 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]. CaV1.2 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.
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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
ICa,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)
- et al.
Analysis of cellular calcium fluxes in cardiac muscle to understand calcium homeostasis in the heart
Cell Calcium
(2007) - et al.
Evolution of calcium homeostasis: from birth of the first cell to an omnipresent signalling system
Cell Calcium
(2007) - 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) - et al.
Determinants for calmodulin binding on voltage-dependent Ca2+ channels
J. Biol. Chem.
(2000) - 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) - 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) - et al.
Transcriptional regulation of L-type calcium channel expression in cardiac myocytes
J. Mol. Cell. Cardiol.
(2000) - et al.
Negative transcriptional regulation of human colonic smooth muscle Cav1.2 channels by p50 and p65 subunits of nuclear factor-kappaB
Gastroenterology
(2005) - et al.
Expression of calcium channels in adult cardiac myocytes is regulated by calcium
J. Mol. Cell. Cardiol.
(1997) - 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)
Expression of multiple CaV1.2 transcripts in rat tissues mediated by different promoters
Cell Calcium
A novel long N-terminal isoform of human L-type Ca2+ channel is up-regulated by protein kinase C
J. Biol. Chem.
A new promoter for alpha1C subunit of human L-type cardiac calcium channel Ca(V)1.2
Biochem. Biophys. Res. Commun.
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.
Different voltage-dependent inhibition by dihydropyridines of human Ca2+ channel splice variants
J. Biol. Chem.
L-type voltage-sensitive calcium channels mediate synaptic activation of immediate early genes
Neuron
Signaling from synapse to nucleus: the logic behind the mechanisms
Curr. Opin. Neurobiol.
Voltage-gated mobility of the Ca2+ channel cytoplasmic tails and its regulatory role
J. Biol. Chem.
The C terminus of the L-type voltage-gated calcium channel ca(v)1.2 encodes a transcription factor
Cell
Unified mechanisms of Ca2+ regulation across the Ca2+ channel family
Neuron
Preassociation of calmodulin with voltage-gated Ca(2+) channels revealed by FRET in single living cells
Neuron
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.
Unchanged beta-adrenergic stimulation of cardiac L-type calcium channels in Ca v 1.2 phosphorylation site S1928A mutant mice
J. Biol. Chem.
cAMP-dependent regulation of cardiac L-type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits
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.
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Roles of L-type calcium channels (Ca<inf>V</inf>1.2) and the distal C-terminus (DCT) in differentiation and mineralization of rat dental apical papilla stem cells (rSCAPs)
2017, Archives of Oral BiologyCitation Excerpt :The accessory β and α2δ subunits can modulate the function of Ca2+ channel by modulating the voltage-dependent properties and the membrane targeting of channel complexes (Hidalgo, Gonzalez-Gutierrez, Garcia-Olivares, & Neely, 2006). Based on the previous studies (Satin, Schroder, & Crump, 2011), the CaV1.2 distal C-terminus is susceptible to proteolytic cleavage, which yield a truncated CaV1.2 subunit and a cleaved C-terminal fragment (CCt or DCT). Additionally, researchers also observed that the DCT fragment could regulate the gene expression as a transcription factor and impair the function of CaV1.2 through interacting with truncated CaV1.2 subunit in cardiac myocytes and neurons (Bannister et al., 2013).
Noncanonical roles of voltage-gated sodium channels
2013, NeuronCitation Excerpt :Interestingly, alternative splicing of some sodium channels, such as Nav1.6, can produce truncated and presumably nonconducting two-domain proteins, which are present in a broad range of nonneuronal tissues (Plummer et al., 1997; Oh and Waxman, 1998). It can also be speculated that further study will uncover nonconducting roles for sodium channels, as has been proposed for the autoregulation of transcription by the C terminus of the L-type calcium channel Cav1.2 (Dolmetsch et al., 2001; Gomez-Ospina et al., 2006; Satin et al., 2011) and tumor progression by the potassium channel ether-á-go-go (Kv10.1) (Downie et al., 2008). It is now clear that many cell types traditionally considered nonexcitable express voltage-gated sodium channels.
Multilayered regulation of cardiac ion channels
2013, Biochimica et Biophysica Acta - Molecular Cell ResearchCitation Excerpt :The CCt was found to re-associate with the truncated channels at the plasma membrane to modulate their activity [98–101]. Recent studies showed that Cav1.2 also functions to couple membrane excitation to gene expression through its CCt, which localizes to the nucleus to regulate transcription [62,63,67]. In neurons and heterologous expression systems, a ~ 300 amino acid CCt fragment was shown to localize to the nucleus in response to calcium signaling to regulate transcription of gap junction proteins such as Cx31.1, potassium channels, the sodium calcium exchanger Scl8A1, and a number of signaling proteins [67].
Ca<sup>2+</sup>-dependent transcriptional control of Ca<sup>2+</sup> homeostasis
2012, Journal of Biological ChemistryCitation Excerpt :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).
Calcium Fluxes and Homeostasis
2012, Muscle: Fundamental Biology and Mechanisms of DiseaseQuantitative aspects of L-type Ca<sup>2+</sup> currents
2012, Progress in NeurobiologyCitation Excerpt :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).