Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. We have previously shown that the activation of either protein kinase A (PKA) or protein kinase C (PKC) enhanced the responses of muscle membrane to acetylcholine (ACh) by increasing the mean open time of embryonic-type ACh channels in Xenopus cultured myocytes. In the present study, we further investigated the interaction between these two kinases in the modulation of ACh channels by using the receptor ligands, adenosine diphosphate (ADP) and calcitonin gene-related peptide (CGRP) which selectively activate PKC and PKA, respectively. 2. ADP concentration-dependently increased the mean open time of embryonic-type ACh channels and 0.3 mM ADP is sufficient to achieve the maximal potentiating effect. alpha, beta-Methylene ATP and PMA (phorbol 12-myristate 13-acetate) but not adenosine, AMP, dibutyryl cyclic GMP have similar potentiating action. 3. Suramin (0.3 mM) pretreatment abolished the potentiating effect of ADP but left that of PMA unchanged. 4. CGRP increased the mean open time of embryonic-type ACh channels in a concentration-dependent manner and 1 microM CGRP produced the maximal effect. 5. The maximal effects of both ADP (0.3 mM) and CGRP (1 microM) in the prolongation of mean open time of ACh channels were additive. 6. These results suggest that the modulation of embryonic-type ACh channels by the endogenously released ligands via the activation of PKA and PKC is additive and possibly different sites of ACh channels may be involved in the potentiation effect of either PKC or PKA.
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PMID:Additive effect of ADP and CGRP in modulation of the acetylcholine receptor channel in Xenopus embryonic myocytes. 758 73

Primary cultures of adult rat dorsal root ganglia (DRG) neurons were used to determine if activation of either the protein kinase A or C signal transduction pathways or treatment with the synthetic glucocorticoid dexamethasone modulate neuronal calcitonin gene-related peptide (CGRP) synthesis and release. DRG are the sites of neuronal cell bodies known to produce abundant CGRP levels, and to send axons peripherally to blood vessels and centrally to the spinal cord. Using immunocytochemical techniques, we confirmed that synthesis of immunoreactive CGRP (iCGRP) is restricted to a subpopulation of DRG neurons. Subsequently, we determined that treatment (24 h) of the neurons with either dibutyryl cAMP (1 mM) or phorbol 12-myristate 13-acetate (2 microM) increased CGRP mRNA content 2.2 +/- 0.4 (n = 6, p < 0.03) and 3.0 +/- 0.6-fold (n = 6, P < 0.02) respectively, while secreted iCGRP levels were increased 1.8 +/- 0.2 (n = 14, P < 0.005) and 4.5 +/- 1.0 (n = 14, P < 0.001)-fold over control levels. Treatment of the neurons with dexamethasone alone had no effect on CGRP expression; however, this agent was able to significantly attenuate the stimulatory effects of NGF on both CGRP mRNA accumulation and release of iCGRP. Time course studies demonstrated that in the phorbol ester treated neurons CGRP mRNA levels continued to increase at 48 h, while maximal induction with dibutyryl cAMP occurred at approximately 12 h. These results indicate that local and/or circulating factors which act through the protein kinase A and C signal transduction pathways upregulate both CGRP expression and release, while glucocorticoids attenuate the stimulatory effects of NGF.
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PMID:Dexamethasone and activators of the protein kinase A and C signal transduction pathways regulate neuronal calcitonin gene-related peptide expression and release. 758 74

Protein phosphorylation is important in synaptic transmission and plasticity. At the neuromuscular junction, phosphorylation of acetylcholine (ACh) receptor-channels increases the rate of agonist-induced channel desensitization. In contrast, potentiation of ACh channel activity through protein phosphorylation has not been described. We report here that calcitonin gene-related peptide (CGRP), a neuropeptide present at presynaptic motor nerve terminals, enhances the postsynaptic response at developing neuromuscular junctions by increasing the burst duration of embryonic ACh channels. The effect of CGRP on these ACh channels is mimicked by dibutyryl-cyclic AMP and by cAMP-dependent protein kinase (PKA) and prevented by a specific peptide inhibitor of PKA. Moreover, postsynaptic inhibition of PKA reduced the amplitude and decay time of spontaneous synaptic currents, suggesting that endogenous CGRP may act as a potentiating factor during the early phase of synaptogenesis.
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PMID:Calcitonin gene-related peptide potentiates synaptic responses at developing neuromuscular junction. 768 14

The signal transduction mechanisms underlying the activation of ATP-sensitive potassium (KATP) current by calcitonin gene-related peptide (CGRP) in gallbladder smooth muscle were examined with intracellular microelectrode recording and whole cell patch-clamp techniques. In the intact gallbladder preparation, the adenylyl cyclase activator forskolin hyperpolarized the membrane potential and abolished spontaneous action potentials. This response was inhibited by the KATP channel blocker glibenclamide. CGRP (10 nM), forskolin (10 microM), the membrane-permeable adenosine 3',5'-cyclic monophosphate (cAMP) analogue adenosine 3',5'-cyclic monophosphothioate (Sp-cAMP[S]; 500 microM), and the catalytic subunit of protein kinase A (100 U/ml) activated glibenclamide-sensitive currents in enzymatically dissociated gallbladder smooth muscle cells. CGRP activation of potassium currents was prevented by dialysis of the cell cytoplasm with guanosine 5'-O-(2-thiodiphosphate) (5 mM) or a specific peptide inhibitor of protein kinase A (2.3 microM). Okadaic acid (5 microM), a phosphatase inhibitor, slowed the deactivation of the KATP current, following removal of CGRP. The results of this study indicate that CGRP hyperpolarizes gallbladder smooth muscle by elevation of cAMP and subsequent stimulation of protein kinase A.
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PMID:Protein kinase A mediates activation of ATP-sensitive K+ currents by CGRP in gallbladder smooth muscle. 794 48

Recent evidence indicates that osteopontin (Opn), one of the bone matrix proteins, plays an important role in the attachment of osteoclasts to bone matrix. Besides being elaborated by osteoblasts, this protein is also produced by osteoclasts. The present study was performed to examine the effect of calcitonin (CT) on Opn mRNA expression of isolated rabbit osteoclasts and to clarify the second messenger signaling of this effect. Eel CT inhibited Opn mRNA expression as well as bone-resorbing activity of isolated rabbit osteoclasts. Eel CT caused a transient increase in intracellular calcium followed by a sustained increase as well as an increase in cAMP production in these cells. Dibutyryl-cAMP (10(-4) M) and Sp-cAMPS (10(-4) M), an activator of cAMP-dependent protein kinase (PKA), as well as A23187 (10(-7) M), a calcium ionophore, and phorbol myristate acetate (10(-7) M), an activator of protein kinase C (PKC), caused a significant inhibition of Opn mRNA expression, and suppressed bone-resorbing activity of isolated osteoclasts. The present study is the first to demonstrate that CT inhibits Opn mRNA expression in isolated rabbit osteoclasts, presumably through the activation of PKA and calcium/PKC pathways, by which the bone-resorbing activity might be attenuated subsequently.
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PMID:Calcitonin inhibits osteopontin mRNA expression in isolated rabbit osteoclasts. 801 90

This editorial review focuses on recent observations regarding the mechanism and regulation of calcium transport in hormone-sensitive distal convoluted tubules. Parathyroid hormone (PTH) and calcitonin increase active calcium absorption by distal convoluted tubules. Occupancy of these peptide hormone receptors results in the activation of both protein kinase A and protein kinase C. The inhibition of either kinase blocks calcium transport. The time course of stimulation of calcium entry in distal convoluted tubules by PTH is slow compared with that by calcitonin. The latency associated with PTH action may be due to the induction of protein synthesis. PTH and calcitonin hyperpolarize membrane voltage, which in turn increases calcium entry. Calcium entry is mediated by calcium channels. These channels exhibit a low, single-channel conductance and are sensitive to dihydropyridine-type calcium channel blockers. Unlike L-type calcium channels, the channel open probability of distal convoluted tubule calcium entry channels is increased upon hyperpolarization. This novel combination of properties suggests that the underlying structure of these calcium entry channels may be unique.
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PMID:Hormone-responsive Ca2+ entry in distal convoluted tubules. 816 21

1. Whole-cell K+ currents activated by calcitonin gene-related peptide (CGRP) in smooth muscle cells enzymatically isolated from rabbit mesenteric arteries were measured in the conventional and perforated configurations of the patch clamp technique. The signal transduction pathway from CGRP receptors to activation of potassium currents was investigated. 2. CGRP (10 nM) activated a whole-cell current that was blocked by glibenclamide (10 microM), an inhibitor of ATP-sensitive K+ channels. Elevating intracellular ATP reduced glibenclamide-sensitive currents. CGRP increased the glibenclamide-sensitive currents by 3- to 6-fold in cells dialysed with 0.1 mM ATP, 3.0 mM ATP or in intact cells. The reversal potential of the glibenclamide-sensitive current in the presence of CGRP shifted with the potassium equilibrium potential, while its current-voltage relationship exhibited little voltage dependence. 3. Forskolin (10 microM), an adenylyl cyclase activator, Sp-cAMPS (500 microM) and the catalytic subunit of protein kinase A increased glibenclamide-sensitive K+ currents 2.1-, 3.3- and 8.2-fold, respectively. 4. Nitric oxide and nitroprusside did not activate glibenclamide-sensitive K+ currents. 5. Dialysis of the cell's interior with inhibitors of protein kinase A (synthetic peptide inhibitor, 4.6 microM or H-8, 100 microM) completely blocked activation of K+ currents by CGRP. 6. Our results suggest the following signal transduction scheme for activation of K+ currents by CGRP in arterial smooth muscle: (1) CGRP stimulates adenylyl cyclase, which leads to an elevation of cAMP; (2) cAMP activates protein kinase A, which opens ATP-sensitive K+ channels.
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PMID:Calcitonin gene-related peptide activated ATP-sensitive K+ currents in rabbit arterial smooth muscle via protein kinase A. 818 94

The present study was performed to compare the effect of parathyroid hormone-related peptide (PTHrP) on bone resorption with that of parathyroid hormone (PTH) and clarify the participation of PTHrP-responsive dual signal transduction systems involving cAMP-dependent protein kinase (PKA) and calcium/protein kinase C (Ca/PKC) in the stimulation of bone resorption by PTHrP. Bone resorbing activity was estimated as the number of pits formed on the dentine slice and total area of pits per slice in bone cells derived from 2 week-old mice. Human (h)PTHrP-(1-34) (10(7) M) stimulated bone resorption as potent as hPTH-(1-34) (10(7) M) did. The stimulation of bone resorption by hPTHrP-(1-34) and hPTH-(1-34) was equally blocked by either simultaneous treatment with 10(-8) M Elcatonin (eel calcitonin derivative; from Asahi Chemical Industry, Tokyo, Japan) [corrected] or pretreatment with 10(-7) M [Nle8,18Tyr34]hPTH-(3-34)amide. Rp-cAMPs, an antagonist in the activation of PKA, equally attenuated bone resorption stimulated by PTHrP as well as by PTH. A23187 (10(-7) M) caused a significant stimulation of bone resorption. These findings indicate the direct involvement of PKA activation and a contributory role of an increase in cytosolic calcium in the stimulation of bone resorption by PTHrP and suggest that PTHrP stimulates bone resorption presumably through the same mechanism as PTH does.
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PMID:Role of dual signal transduction systems in the stimulation of bone resorption by parathyroid hormone-related peptide. The direct involvement of cAMP-dependent protein kinase. 822 86

1. The involvement of calcitonin gene-related peptide (CGRP) in the mechanism of nicotinic acetylcholine receptor-operated noncontractile Ca2+ mobilization (not accompanied by twitch tension) was investigated by measuring Ca(2+)-aequorin luminescence at the neuromuscular junction of mouse diaphragm muscle treated with neostigmine. 2. Noncontractile Ca2+ transients were enhanced by 4-aminopyridine (100 microM), a K+ channel blocker, and inhibited by botulinum toxin (1-100 micrograms, i.p.) and hexamethonium (10-100 microM), a neuronal nicotinic receptor antagonist. 3. Noncontractile Ca2+ transients were diminished by CGRP8-37 (10-20 microM), a CGRP antagonist. CGRP (0.3-10 nM) prolonged the duration of noncontractile Ca2+ transients. The effect of CGRP was suppressed by CGRP8-37 (0.1 microM). 4. Noncontractile Ca2+ transients were inhibited by H-89 (0.1-1 microM), a protein kinase-A inhibitor. The catalytic subunit of protein kinase-A and AA373 (300 microM), a protein kinase-A activator, prolonged the duration of noncontractile transients. The prolongations either by CGRP or by AA373 were not observed in the presence of H-89 (0.1 microM). 5. Contractile (accompanied by twitch tension) but not noncontractile Ca2+ transients were decreased by 12-O-tetradecanoyl phorbol 13-acetate (TPA, 0.3-1 microM), a protein kinase-C activator. Phospholipase A2 increased only contractile Ca2+ transients. Calmodulin-related agents affected neither type of Ca2+ transients. 6. These results provide the first evidence that nicotinic acetylcholine receptor-operated noncontractile Ca2+ mobilization is promoted by nerve-released CGRP activating protein kinase-A, and is dependent on the accumulated amounts of acetylcholine at the neuromuscular junction where desensitization might readily develop.
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PMID:Enhancement by calcitonin gene-related peptide of nicotinic receptor-operated noncontractile Ca2+ mobilization at the mouse neuromuscular junction. 824 36

The aim of the present study was to examine the effects of calcitonin gene-related peptide (CGRP) on the K+ channels of vascular smooth muscle cells. Cultured smooth muscle cells from a porcine coronary artery were studied using the patch-clamp technique. Extracellular application of 100 nM CGRP activated two types of K+ channels, the Ca(2+)-activated K+ channel (KCa channel) and the ATP-sensitive K+ channel (KATP channel) in cell-attached patch configurations. In cells pretreated with Rp-cAMPS, a membrane-permeable inhibitor of cAMP-dependent protein kinase (PKA), extracellular application of 100 nM CGRP could not activate the KCa or KATP channel, indicating that the activation of the K+ channels by CGRP occurs in connection with PKA. In the cell-attached patch configurations, extracellular application of 1 mM dibutyryl cAMP, a membrane permeable cAMP, activated KCa and KATP channels. In inside-out patch configurations, application of PKA to the cytosolic side activated both the KCa and KATP channels. These results indicate that CGRP modulates the K+ channels of vascular smooth muscle cells via adenylate cyclase, i.e., cAMP-PKA pathway, and contributes to control of vascular tone.
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PMID:Calcitonin gene-related peptide activates the K+ channels of vascular smooth muscle cells via adenylate cyclase. 853 58


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