G Protein Modulation of Voltage-Gated Calcium Channels

Dolphin, Annette C.

doi:10.1124/pr.55.4.3

Cited by 267 publications

(226 citation statements)

References 194 publications

(283 reference statements)

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“…For example, mutations in basic residues reduced G␤␥ binding to ␤-adrenergic receptor kinase 1 and phospholipase C␤3 (21,22). Furthermore, similar results were obtained with mutations in the N-terminal region and in the cytoplasmic linker between the first and second transmembrane repeats of voltage-gated calcium channels (19,20,23).…”

supporting

confidence: 67%

“…Biochemical and functional data studies determined multiple binding and modulatory sites in voltage-gated calcium channels and GIRK channels, indicating a high degree of complexity (19,20,23,35,36). Despite this, the presence of basic residues inside the critical regions for binding and modulation appears to be a common feature.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, some molecular characteristics for binding and modulation of G␤␥ to other effector proteins are better understood (17)(18)(19). In fact, previous studies implicated the presence of basic amino acids, such as lysine and arginine, in the modulation of voltage-gated calcium channels, phospholipase C␤, and ␤-adrenergic receptor kinases (20 -23).…”

mentioning

confidence: 99%

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Molecular Determinants for G Protein βγ Modulation of Ionotropic Glycine Receptors

Yévenes

Moraga-Cid

Guzmán

et al. 2006

Journal of Biological Chemistry

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The ligand-gated ion channel superfamily plays a critical role in neuronal excitability. The functions of glycine receptor (GlyR) and nicotinic acetylcholine receptor are modulated by G protein ␤␥ subunits. The molecular determinants for this functional modulation, however, are still unknown. Studying mutant receptors, we identified two basic amino acid motifs within the large intracellular loop of the GlyR ␣ 1 subunit that are critical for binding and functional modulation by G␤␥. Mutations within these sequences demonstrated that all of the residues detected are important for G␤␥ modulation, although both motifs are necessary for full binding. Molecular modeling predicts that these sites are ␣-helixes near transmembrane domains 3 and 4, near to the lipid bilayer and highly electropositive. Our results demonstrate for the first time the sites for G protein ␤␥ subunit modulation on GlyRs and provide a new framework regarding the ligand-gated ion channel superfamily regulation by intracellular signaling.The ionotropic glycine receptors (GlyRs) 2 are members of the ligand-gated ion receptor superfamily, which includes inhibitory ␥-aminobutyric acid type A receptors and excitatory nAChR and 5-HT 3 receptors. These homologous receptors mediate fast synaptic transmission in the central nervous system (1, 2). Inhibitory GlyRs are critical for the control of excitability in the mammalian spinal cord and brain stem. Binding of glycine to the extracellular region induces a rapid increase in Cl Ϫ ion conductance, generating a hyperpolarization of the cell membrane (3-5). In neurons, the inhibitory action of GlyRs regulate several important physiological functions, like pain transmission, respiratory rhythms, motor coordination, and development (3-7). Like all members of the LGIC superfamily, GlyRs are pentamers composed of five subunits in which each subunit possesses four transmembrane domains arranged to form the ion pore. In this structure, the individual subunits provide extracellular and intracellular domains that play roles in ligand binding and intracellular modulation, respectively (1-3, 5).The function of GlyRs can be effectively modulated by extracellularly acting compounds like strychnine, picrotoxin, zinc ions, and ethanol (3-5, 8, 9). Furthermore, the receptor can also be modulated by intracellular signaling. One of the most studied and recognized pathways involved in regulation of ligandgated ion channel function are phosphorylation processes through protein kinases. Indeed, GlyR and other members of the LGIC superfamily are modulated by activation of cAMPdependent kinases and protein kinase C (10). This involves specific serine residues in the loop between transmembrane domains 3 and 4 (6, 10 -14). On the other hand, recent reports have shown that the activity of GlyRs and nAChRs can be modulated by G protein ␤␥ subunits in a phosphorylation-independent manner (15, 16). In both cases, activation of G proteins, using nonhydrolyzable GTP analogs or by application of purified G␤␥ dimers, generates a strong e...

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supporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular Determinants for G Protein βγ Modulation of Ionotropic Glycine Receptors

Yévenes

Moraga-Cid

Guzmán

et al. 2006

Journal of Biological Chemistry

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“…While it is well established that the Gβγ dimer inhibits N-type Ca 2+ -channel activity [29], Gβγ may also inhibit presynaptic L-type Ca 2+ -channels [30;31]. Further, Gβγ i is known to decrease adenylyl cyclase activity [32].…”

Section: Discussionmentioning

confidence: 99%

Histamine H3-receptor signaling in cardiac sympathetic nerves: Identification of a novel MAPK-PLA2-COX-PGE2-EP3R pathway

Levi

Seyedi

Schäefer

et al. 2007

Biochemical Pharmacology

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We tested the hypothesis that the histamine H 3 -receptor (H 3 R)-mediated attenuation of norepinephrine (NE) exocytosis from cardiac sympathetic nerves results not only from a Gα imediated inhibition of the adenylyl cyclase-cAMP-PKA pathway, but also from a Gβγ i -mediated activation of the MAPK-PLA 2 cascade, culminating in formation of an arachidonate metabolite with anti-exocytotic characteristics (e.g., PGE 2 ). We report in Langendorff-perfused guinea-pig hearts and isolated sympathetic nerve endings (cardiac synaptosomes), H 3 R-mediated attenuation of K + -induced NE exocytosis was prevented by MAPK and PLA 2 inhibitors, and by cyclooxygenase and EP 3 -receptor (EP 3 R) antagonists. Moreover, H 3 R activation resulted in MAPK phosphorylation in H 3 R-transfected SH-SY5Y neuroblastoma cells, and in PLA 2 activation and PGE 2 production in cardiac synaptosomes; H 3 R-induced MAPK phosphorylation was prevented by an anti-βγ peptide. Synergism between H 3 R and EP 3 R agonists (i.e., imetit and sulprostone, respectively) suggested PGE 2 may be a downstream effector of the anti-exocytotic effect of H 3 R activation. Furthermore, the anti-exocytotic effect of imetit and sulprostone was potentiated by the N-type Ca 2+ -channel antagonist ω-conotoxin GVIA, and prevented by an anti-Gβγ peptide. Our findings suggest an EP 3 R Gβγ i -induced decrease in Ca 2+ influx through N-type Ca 2+ -channels is involved in PGE 2 / EP 3 R-mediated attenuation of NE exocytosis elicited by H 3 R activation. Conceivably, activation of the Gβγ i subunit of H 3 R and EP 3 R may also inhibit Ca 2+ entry directly, independent of MAPK intervention. As heart failure, myocardial ischemia and arrhythmic dysfunction are associated with excessive local NE release, attenuation of NE release by H 3 R activation is cardioprotective. Thus, the uncovering of a novel H 3 R signaling pathway may ultimately bear therapeutic significance in hyper-adrenergic states.

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“…CaV␤ proteins are ϳ500 amino acid cytoplasmic proteins that bind to the CaV␣ 1 I-II intracellular loop (9) and affect channel gating properties (4), trafficking (10,11), regulation by neurotransmitter receptors through G-protein ␤␥ subunit activation (12), and sensitivity to drugs (13). The CaV␤ primary sequence encodes five domains, arranged V1-C1-V2-C2-V3.…”

mentioning

confidence: 99%

Diversity and Developmental Expression of L-type Calcium Channel β2 Proteins and Their Influence on Calcium Current in Murine Heart

Link

Meissner

Held³

et al. 2009

Journal of Biological Chemistry

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By now, little is known on L-type calcium channel (LTCC) subunits expressed in mouse heart. We show that CaV␤2 proteins are the major CaV␤ components of the LTCC in embryonic and adult mouse heart, but that in embryonic heart CaV␤3 proteins are also detectable. At least two CaV␤2 variants of ϳ68 and ϳ72 kDa are expressed. To identify the underlying CaV␤2 variants, cDNA libraries were constructed from poly(A) ؉ RNA isolated from hearts of 7-day-old and adult mice. Screening identified 60 independent CaV␤2 cDNA clones coding for four types of CaV␤2 proteins only differing in their 5 sequences. CaV␤2-N1, -N4, and -N5 but not -N3 were identified in isolated cardiomyocytes by RT-PCR and were sufficient to reconstitute the CaV␤2 protein pattern in vitro. Significant L-type Ca 2؉ currents (I Ca ) were recorded in HEK293 cells after co-expression of CaV1.2 and CaV␤2. Current kinetics were determined by the type of CaV␤2 protein, with the ϳ72-kDa CaV␤2a-N1 shifting the activation of I Ca significantly to depolarizing potentials compared with the other CaV␤2 variants. Inactivation of I Ca was accelerated by CaV␤2a-N1 and -N4, which also lead to slower activation compared with CaV␤2a-N3 and -N5. In summary, this study reveals the molecular LTCC composition in mouse heart and indicates that expression of various CaV␤2 proteins may be used to adapt the properties of LTCCs to changing myocardial requirements during development and that CaV␤2a-N1-induced changes of I Ca kinetics might be essential in embryonic heart.

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G Protein Modulation of Voltage-Gated Calcium Channels

Cited by 267 publications

References 194 publications

Molecular Determinants for G Protein βγ Modulation of Ionotropic Glycine Receptors

Molecular Determinants for G Protein βγ Modulation of Ionotropic Glycine Receptors

Histamine H3-receptor signaling in cardiac sympathetic nerves: Identification of a novel MAPK-PLA2-COX-PGE2-EP3R pathway

Diversity and Developmental Expression of L-type Calcium Channel β2 Proteins and Their Influence on Calcium Current in Murine Heart

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