scholarly journals Integrin Receptor Activation Triggers Converging Regulation of Cav1.2 Calcium Channels by c-Src and Protein Kinase A Pathways

2006 ◽  
Vol 281 (20) ◽  
pp. 14015-14025 ◽  
Author(s):  
Peichun Gui ◽  
Xin Wu ◽  
Shizhang Ling ◽  
Stephanie C. Stotz ◽  
Robert J. Winkfein ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Calcium Channels ◽  
Protein Kinase A ◽  
Receptor Activation ◽  
Integrin Receptor ◽  
Kinase A

Baclofen inhibition of the hyperpolarization-activated cation current, Ih, in rat substantia nigra zona compacta neurons may be secondary to potassium current activation

1996 ◽  
Vol 76 (4) ◽  
pp. 2262-2270 ◽  
Author(s):  
A. E. Watts ◽  
J. T. Williams ◽  
G. Henderson
Keyword(s):  
Protein Kinase ◽  
Substantia Nigra ◽  
Protein Kinase A ◽  
Potassium Current ◽  
Gabab Receptor ◽  
Reversal Potential ◽  
Membrane Conductance ◽  
Receptor Activation ◽  
Cation Current ◽  
Kinase A

1. The properties of the hyperpolarization-activated cation current (Ih), and its modulation by gamma-aminobuturic acid-B (GABAB) receptor activation and protein kinase A, were investigated using whole cell voltage clamp of substantia nigra zona compacta principal neurons in rat midbrain slices in vitro. 2. At 30 degrees C, Ih activated between -75 and -155 mV, with a V1/2 of -115 mV. At 35 degrees C, the activation curve shifted positive by 10 mV. Ih had an estimated reversal potential of -27 mV. Ion substitution experiments showed that the current was carried by Na+ and K+. 3. Application of the GABAB receptor agonist baclofen (30 microM) induced an outward potassium current (GIRK), increased neuronal membrane conductance and inhibited Ih. The inhibition of Ih was voltage independent. Baclofen induced an 11-mV positive shift in the reversal potential of Ih. 4. Extracellular barium (300 microM) markedly reduced the baclofen-evoked outward current and associated increase in membrane conductance due to GIRK activation. There was also very little inhibition of Ih by baclofen in the presence of barium. When cesium was the major intracellular cation, both the increase in membrane conductance due to GIRK activation and the inhibition of Ih evoked by baclofen were reduced by a similar extent. 5. Neither forskolin (10 microM) nor the protein kinase A inhibitor, H89 (10 microM), had any effect on Ih or its inhibition by baclofen. 6. These data suggest that the inhibition of Ih by baclofen is secondary to the activation of GIRK, i.e., due directly to alteration of membrane conductance, rather than a distinct effect, and is not mediated by inhibition of adenylyl cyclase.

scholarly journals Protein kinase A modulation of CaV1.4 calcium channels

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Lingjie Sang ◽  
Ivy E. Dick ◽  
David T. Yue
Keyword(s):  
Protein Kinase ◽  
Calcium Channels ◽  
Protein Kinase A ◽  
Kinase A

A2 adenosine receptors regulate CFTR through PKA and PLA2

2002 ◽  
Vol 282 (1) ◽  
pp. L12-L25 ◽  
Author(s):  
B. R. Cobb ◽  
F. Ruiz ◽  
C. M. King ◽  
J. Fortenberry ◽  
H. Greer ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Receptor Activation ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Δf508 Cftr ◽  
Kinase A

We investigated adenosine (Ado) activation of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro and in vivo. A2B Ado receptors were identified in Calu-3, IB-3-1, COS-7, and primary human airway cells. Ado elevated cAMP in Calu-3, IB-3-1, and COS-7 cells and activated protein kinase A-dependent halide efflux in Calu-3 cells. Ado promoted arachidonic acid release from Calu-3 cells, and phospholipase A2(PLA2) inhibition blocked Ado-activated halide efflux in Calu-3 and COS-7 cells expressing CFTR. Forskolin- and β2-adrenergic receptor-stimulated efflux were not affected by the same treatment. Cytoplasmic PLA2(cPLA2) was identified in Calu-3, IB-3-1, and COS-7 cells, but cPLA2 inhibition did not affect Ado-stimulated cAMP concentrations. In cftr(+) and cftr(−/−) mice, Ado stimulated nasal Cl− secretion that was CFTR dependent and sensitive to A2 receptor and PLA2 blockade. In COS-7 cells transiently expressing ΔF508 CFTR, Ado activated halide efflux. Ado also activated G551D CFTR-dependent halide efflux when combined with arachidonic acid and phosphodiesterase inhibition. In conclusion, PLA2 and protein kinase A both contribute to A2 receptor activation of CFTR, and components of this signaling pathway can augment wild-type and mutant CFTR activity.

scholarly journals Regulation of Cardiac L-Type Ca 2+ Channel Ca V 1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway

2013 ◽  
Vol 113 (5) ◽  
pp. 617-631 ◽  
Author(s):  
Sharon Weiss ◽  
Shimrit Oz ◽  
Adva Benmocha ◽  
Nathan Dascal
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Adrenergic Receptor ◽  
Transgenic Animals ◽  
Receptor Activation ◽  
Model Systems ◽  
Adrenergic Stimulation ◽  
New Findings ◽  
Kinase A

In the heart, adrenergic stimulation activates the β-adrenergic receptors coupled to the heterotrimeric stimulatory G s protein, followed by subsequent activation of adenylyl cyclase, elevation of cyclic AMP levels, and protein kinase A (PKA) activation. One of the main targets for PKA modulation is the cardiac L-type Ca 2+ channel (Ca V 1.2) located in the plasma membrane and along the T-tubules, which mediates Ca 2+ entry into cardiomyocytes. β-Adrenergic receptor activation increases the Ca 2+ current via Ca V 1.2 channels and is responsible for the positive ionotropic effect of adrenergic stimulation. Despite decades of research, the molecular mechanism underlying this modulation has not been fully resolved. On the contrary, initial reports of identification of key components in this modulation were later refuted using advanced model systems, especially transgenic animals. Some of the cardinal debated issues include details of specific subunits and residues in Ca V 1.2 phosphorylated by PKA, the nature, extent, and role of post-translational processing of Ca V 1.2, and the role of auxiliary proteins (such as A kinase anchoring proteins) involved in PKA regulation. In addition, the previously proposed crucial role of PKA in modulation of unstimulated Ca 2+ current in the absence of β-adrenergic receptor stimulation and in voltage-dependent facilitation of Ca V 1.2 remains uncertain. Full reconstitution of the β-adrenergic receptor signaling pathway in heterologous expression systems remains an unmet challenge. This review summarizes the past and new findings, the mechanisms proposed and later proven, rejected or disputed, and emphasizes the essential issues that remain unresolved.

Cross Talk Between A1 and A2A Adenosine Receptors in the Hippocampus and Cortex of Young Adult and Old Rats

1999 ◽  
Vol 82 (6) ◽  
pp. 3196-3203 ◽  
Author(s):  
Luísa V. Lopes ◽  
Rodrigo A. Cunha ◽  
J. A. Ribeiro
Keyword(s):  
Protein Kinase C ◽  
Young Adult ◽  
Protein Kinase ◽  
Synaptic Transmission ◽  
Protein Kinase A ◽  
Receptor Activation ◽  
Cgs 21680 ◽  
Kinase C ◽  
Population Spike Amplitude ◽  
Kinase A

Adenosine modulates synaptic transmission by acting on inhibitory A1 and facilitatory A2A receptors, the densities of which are modified in aged animals. We investigated how A2A receptor activation influences A1receptor function and whether this interaction is modified in aged rats. In hippocampal and cortical nerve terminals from young adult (6 wk), but not old rats (24 mo), the A2A receptor agonist, 2-[4-(2-carboxyethyl) phenethylamino]-5′- N-ethylcarboxamidoadenosine (CGS 21680; 30 nM) decreased the binding affinity of a selective A1 receptor agonist, cyclopentyladenosine (CPA), an effect prevented by the A2A antagonist, (4-(2-[7-amino-2-(2-furyl {1,2,4}-triazolo{2,3-a {1,3,5}triazin-5-yl-aminoethyl)phenol (ZM 241385, 20 nM). This effect of CGS 21680 required intact nerve terminals and was also observed in the absence of Ca2+. This A2A-induced “desensitization” of A1receptors was prevented by the protein kinase C inhibitor, chelerythrine (6 μM), and was not detected in the presence of the protein kinase C activator, phorbol-12,13-didecanoate (250 nM), which itself caused a reduction in binding affinity for CPA. The protein kinase A inhibitor, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (10 μM), and the protein kinase A activator, 8-Br-cAMP (1 mM), had no effects on the A2A-induced A1 receptor desensitization. This A2A-induced A1 receptor desensitization had a functional correlation because CGS 21680 (10 nM) attenuated by 40% the inhibition caused by CPA (10 nM) on CA1 area population spike amplitude in hippocampal slices. This A2A/A1 interaction may explain the attenuation by adenosine deaminase (2 U/ml), which removes tonic A1inhibition, of the facilitatory effect of CGS 21680 on synaptic transmission. The requirement of tonic A1 receptor activation for CGS 21680 to induce facilitation of synaptic transmission was reinforced by the observation that the A1receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (20 nM) prevented CGS 21680 (10 nM) facilitation of population spike amplitude. The present results show the ability of A2A receptors to control A1 receptor function in a manner mediated by protein kinase C, but not protein kinase A, in young adult but not in aged rats.

Bupivacaine Inhibits Activation of Neuronal Spinal Extracellular Receptor–activated Kinase through Selective Effects on Ionotropic Receptors

2006 ◽  
Vol 104 (4) ◽  
pp. 805-814 ◽  
Author(s):  
Fumi Yanagidate ◽  
Gary R. Strichartz
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Substance P ◽  
Protein Kinase A ◽  
Dorsal Horn ◽  
Receptor Activation ◽  
Metabotropic Receptors ◽  
Metabotropic Receptor ◽  
Kinase C ◽  
Kinase A

Background Central terminals of primary nociceptors release neurotransmitters glutamate and substance P, which bind to ionotropic or metabotropic receptors on spinal neurons to induce cellular responses. Extracellular signal-regulated kinases are activated by these receptors and are important modulators of pain at the dorsal horn. The authors investigated these pathways as potential targets for antinociceptive actions of local anesthetics. Methods The effects of bupivacaine on the activation of extracellular receptor-activated kinase (phosphorylation to pERK) in rat spinal cord slices, induced by presynaptic release (capsaicin), by presynaptic or postsynaptic ionotropic or metabotropic receptor activation, or by activation of intracellular protein kinase C or protein kinase A and also by a receptor-independent Ca2+ ionophore, were quantitated by immunohistochemistry, counting pERK-positive neurons in the superficial dorsal horn. Results Capsaicin (3 microm, 10 min)-stimulated pERK was reduced by bupivacaine (IC50 approximately 2 mm, approximately 0.05%), which similarly suppressed pERK induced by the ionotropic glutamate receptors for N-methyl-D-aspartate and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid but not that induced by the metabotropic receptors for glutamate, bradykinin, or substance P. Extracellular receptor-activated kinase activation by the Ca2+ ionophore ionomycin was also sensitive to bupivacaine, but direct activation by protein kinase A or protein kinase C was not. Conclusions Bupivacaine inhibits pERK activation resulting from different modes of Ca2+ influx through the plasma membrane. This represents a postsynaptic mechanism of analgesia that occurs in parallel with impulse inhibition during neuraxial blockade.

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