Calcium-Dependent Protein Phosphorylation View Full Text


Ontology type: schema:Chapter     


Chapter Info

DATE

1982

AUTHORS

H. Schulman

ABSTRACT

OverviewIn recent years there has been renewed appreciation of the importance of calcium in various modes of cell activation. It is becoming apparent that one can no longer separate the individual contributions of calcium and of the cyclic nu-cleotides in regulating the cellular responses of a variety of neuronal and hormonal stimuli. Although the actions of calcium do not appear to be mediated by a universal biochemical mechanism, this review considers the possibility that certain of the physiological effects of calcium may be mediated or modulated by protein phosphorylation.The mechanisms involved in regulation of liver carbohydrate metabolism by catecholamines, vasopressin, and angiotensin are assessed. The role of a-adrenergic and β-adrenergic receptors in mediating the response to catecholamines appears to be species dependent. In rat liver, activation of the cAMP-dependent protein kinase does not appear to be necessary for stimulating glycogenolysis by epinephrine. The β-adrenergic receptor antagonist, propranolol, has no effect on epinephrine-stimulated glycogenolysis, while abolishing epinephrine-stimulated increases in cAMP. Conversely, phenoxybenzamine, an α-adrenergic receptor antagonist, blocks the effect of epinephrine on glycogenolysis without any effect on cAMP levels. cAMP-independent pathways are also suggested by studies on regulation of carbohydrate metabolism by vasopressin and angiotensin II. There is no evidence for the involvement of cGMP in any of these systems. Indeed, there is strong evidence that increased calcium levels resulting either from influx or from redistribution of intracellular stores may regulate glycogenolysis in these systems. Some of the effects of these hormones may result from activation of calcium-dependent protein kinases.Calcium-dependent protein phosphorylation has now been demonstrated in several intact systems. These include synaptosomes, brain slices, mast cells, and isolated hepatocytes. Studies on synaptosomes, or pinched off nerve endings, indicate that depolarization by various agents leads to a calcium-dependent increase in the incorporation of [32P]O4 into several proteins. Such calcium-dependent protein phosphorylation may be involved in neurotransmitter synthesis or release. The possibility that release processes may in general be associated with calcium-stimulated changes in protein phosphorylation is strengthened by the studies showing changes in protein phosphorylation in mast cells stimulated by the secretagogue 48/80.Studies with isolated hepatocytes demonstrate that although the actions of catecholamines, vasopressin, and angiotensin II on carbohydrate metabolism do not involve changes in cyclic nucleotide levels, stimulation of the cells by these hormones is accompanied by increased incorporation of [32P]O4 into various proteins, including pyruvate kinase and phosphorylase. Most of the proteins whose phosphorylation is regulated by these hormones are also regulated by glucagon, whose action is mediated by cAMP-dependent phosphorylation.Four calcium dependent protein kinases are examined in detail. The effects of calcium on protein phosphorylation in synaptosomes may be mediated by a membrane-bound calcium-dependent protein kinase. This protein kinase requires an endogenous cytosolic, heat-stable protein for activity. This protein is shown to be identical to calmodulin, a ubiquitous calcium-binding protein, known to be involved in regulation of a variety of calcium-dependent processes. Authentic calmodulin and the endogenous protein kinase activator have identical physico-chemical characteristics, including activation of protein phosphorylation, sensitivity to calcium, and amino acid composition.Protein I, one of the proteins phosphorylated in intact synaptosomes, is also phosphorylated in membrane fractions. Its phosphorylation in intact and lysed synaptosomes is regulated by cAMP and by calcium at distinct sites on the protein. In intact synaptosomes, 8-Br-cAMP stimulates phosphorylation of the cAMP-regulated site(s) while reducing phosphorylation of the calciumregulated site(s). Thus, some of the actions of these two second messengers on neuronal function may intersect at the level of protein phosphorylation.The calmodulin- and calcium-dependent protein phosphorylation system is not confined to brain but has a widespread distribution in membranes from a variety of rat tissues. Each tissue displays a tissue specific array of endogenous substrate proteins, consistent with the possibility that this phosphorylation system regulates specific effects of calcium in each of the tissues.Myosin light chain kinase from skeletal muscle, smooth muscle, and a variety of nonmuscle cells, including platelets, baby hamster kidney cells, and brain cells is a calcium-dependent protein kinase which also requires calmodulin for activity. In vivo studies indicate that the state of phosphorylation of the P-light chain of myosin is changed during muscular activity. In smooth muscle, phosphorylation of myosin light chains can be directly correlated with ATPase activity and tension development. The function of myosin light chain kinase in skeletal muscle is not well understood. Phosphorylation of myosin light chain kinase by a cAMP-dependent protein kinase reduces its activity, providing a locus for interaction of calcium and cAMP in regulating muscle contraction.Phosphorylase kinase, long known to be a calcium-dependent enzyme, has recently been shown to contain calmodulin as one of its intrinsic subunits. Unlike other calmodulin-dependent enzymes, the calmodulin in phosphorylase kinase does not dissociate from the enzyme complex in the absence of calcium. However, each tetrameric enzyme has four additional calmodulin binding sites which reversibly interact with calmodulin, leading to additional stimulation of the enzyme. Recent studies indicate that glycogen synthase may also be a substrate for phosphorylase kinase. Thus, this enzyme may account for some of the calcium-dependent phosphorylation observed in liver and other tissues. Regulation of phosphorylase kinase in vivo and in vitro by calcium and by cAMP is discussed.A protein kinase with broad specificity has recently been identified in a variety of mammalian tissues. This cAMP-independent protein kinase is activated by calcium via two independent mechanisms. At relatively high calcium concentrations a neutral protease is able to convert the proenzyme of this protein kinase to a smaller active form. At lower calcium concentrations this enzyme can be activated without proteolysis if a membrane-associated factor or one of several purified phospholipids is present. The activated enzyme can phosphorylate phosphorylase kinase, glycogen synthase, and various histones.The physiological and biochemical studies on intact tissue suggest the presence of cAMP-independent, calcium-dependent protein phosphorylation. The four calcium-dependent protein kinases discussed above may be involved in mediating or modulating some calcium-dependent physiological processes. The action of cAMP-dependent and calcium-dependent protein kinases on the same substrate proteins or on functionally related proteins may provide an interface for the interaction of these two second messenger systems. More... »

PAGES

425-478

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/978-3-642-68111-0_13

DOI

http://dx.doi.org/10.1007/978-3-642-68111-0_13

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The possibility that release processes may in general be associated with calcium-stimulated changes in protein phosphorylation is strengthened by the studies showing changes in protein phosphorylation in mast cells stimulated by the secretagogue 48/80.Studies with isolated hepatocytes demonstrate that although the actions of catecholamines, vasopressin, and angiotensin II on carbohydrate metabolism do not involve changes in cyclic nucleotide levels, stimulation of the cells by these hormones is accompanied by increased incorporation of [32P]O4 into various proteins, including pyruvate kinase and phosphorylase. Most of the proteins whose phosphorylation is regulated by these hormones are also regulated by glucagon, whose action is mediated by cAMP-dependent phosphorylation.Four calcium dependent protein kinases are examined in detail. The effects of calcium on protein phosphorylation in synaptosomes may be mediated by a membrane-bound calcium-dependent protein kinase. 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8 schema:description OverviewIn recent years there has been renewed appreciation of the importance of calcium in various modes of cell activation. It is becoming apparent that one can no longer separate the individual contributions of calcium and of the cyclic nu-cleotides in regulating the cellular responses of a variety of neuronal and hormonal stimuli. Although the actions of calcium do not appear to be mediated by a universal biochemical mechanism, this review considers the possibility that certain of the physiological effects of calcium may be mediated or modulated by protein phosphorylation.The mechanisms involved in regulation of liver carbohydrate metabolism by catecholamines, vasopressin, and angiotensin are assessed. The role of a-adrenergic and β-adrenergic receptors in mediating the response to catecholamines appears to be species dependent. 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Some of the effects of these hormones may result from activation of calcium-dependent protein kinases.Calcium-dependent protein phosphorylation has now been demonstrated in several intact systems. These include synaptosomes, brain slices, mast cells, and isolated hepatocytes. Studies on synaptosomes, or pinched off nerve endings, indicate that depolarization by various agents leads to a calcium-dependent increase in the incorporation of [32P]O4 into several proteins. Such calcium-dependent protein phosphorylation may be involved in neurotransmitter synthesis or release. 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This protein kinase requires an endogenous cytosolic, heat-stable protein for activity. This protein is shown to be identical to calmodulin, a ubiquitous calcium-binding protein, known to be involved in regulation of a variety of calcium-dependent processes. Authentic calmodulin and the endogenous protein kinase activator have identical physico-chemical characteristics, including activation of protein phosphorylation, sensitivity to calcium, and amino acid composition.Protein I, one of the proteins phosphorylated in intact synaptosomes, is also phosphorylated in membrane fractions. Its phosphorylation in intact and lysed synaptosomes is regulated by cAMP and by calcium at distinct sites on the protein. In intact synaptosomes, 8-Br-cAMP stimulates phosphorylation of the cAMP-regulated site(s) while reducing phosphorylation of the calciumregulated site(s). Thus, some of the actions of these two second messengers on neuronal function may intersect at the level of protein phosphorylation.The calmodulin- and calcium-dependent protein phosphorylation system is not confined to brain but has a widespread distribution in membranes from a variety of rat tissues. Each tissue displays a tissue specific array of endogenous substrate proteins, consistent with the possibility that this phosphorylation system regulates specific effects of calcium in each of the tissues.Myosin light chain kinase from skeletal muscle, smooth muscle, and a variety of nonmuscle cells, including platelets, baby hamster kidney cells, and brain cells is a calcium-dependent protein kinase which also requires calmodulin for activity. In vivo studies indicate that the state of phosphorylation of the P-light chain of myosin is changed during muscular activity. In smooth muscle, phosphorylation of myosin light chains can be directly correlated with ATPase activity and tension development. The function of myosin light chain kinase in skeletal muscle is not well understood. Phosphorylation of myosin light chain kinase by a cAMP-dependent protein kinase reduces its activity, providing a locus for interaction of calcium and cAMP in regulating muscle contraction.Phosphorylase kinase, long known to be a calcium-dependent enzyme, has recently been shown to contain calmodulin as one of its intrinsic subunits. Unlike other calmodulin-dependent enzymes, the calmodulin in phosphorylase kinase does not dissociate from the enzyme complex in the absence of calcium. However, each tetrameric enzyme has four additional calmodulin binding sites which reversibly interact with calmodulin, leading to additional stimulation of the enzyme. Recent studies indicate that glycogen synthase may also be a substrate for phosphorylase kinase. Thus, this enzyme may account for some of the calcium-dependent phosphorylation observed in liver and other tissues. Regulation of phosphorylase kinase in vivo and in vitro by calcium and by cAMP is discussed.A protein kinase with broad specificity has recently been identified in a variety of mammalian tissues. This cAMP-independent protein kinase is activated by calcium via two independent mechanisms. At relatively high calcium concentrations a neutral protease is able to convert the proenzyme of this protein kinase to a smaller active form. At lower calcium concentrations this enzyme can be activated without proteolysis if a membrane-associated factor or one of several purified phospholipids is present. The activated enzyme can phosphorylate phosphorylase kinase, glycogen synthase, and various histones.The physiological and biochemical studies on intact tissue suggest the presence of cAMP-independent, calcium-dependent protein phosphorylation. The four calcium-dependent protein kinases discussed above may be involved in mediating or modulating some calcium-dependent physiological processes. The action of cAMP-dependent and calcium-dependent protein kinases on the same substrate proteins or on functionally related proteins may provide an interface for the interaction of these two second messenger systems.
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95 endogenous cytosolic
96 endogenous substrate proteins
97 enzyme
98 enzyme complex
99 epinephrine
100 epinephrine-stimulated glycogenolysis
101 epinephrine-stimulated increase
102 evidence
103 factors
104 form
105 fraction
106 function
107 glucagon
108 glycogen synthase
109 glycogenolysis
110 hamster kidney cells
111 heat-stable protein
112 hepatocytes
113 high calcium concentrations
114 histones
115 hormonal stimuli
116 hormone
117 importance
118 importance of calcium
119 incorporation
120 increase
121 independent mechanisms
122 individual contributions
123 influx
124 intact synaptosomes
125 intact system
126 intact tissue
127 interaction
128 interaction of calcium
129 interface
130 intracellular stores
131 intrinsic subunits
132 involvement
133 involvement of cGMP
134 kidney cells
135 kinase
136 kinase activator
137 levels
138 light chain
139 light chain kinase
140 liver
141 liver carbohydrate metabolism
142 loci
143 low calcium concentrations
144 lysed synaptosomes
145 mammalian tissues
146 mast cells
147 mechanism
148 membrane
149 membrane fraction
150 membrane-associated factors
151 messenger
152 messenger systems
153 metabolism
154 mode
155 muscle
156 muscle contraction
157 muscular activity
158 myosin
159 myosin light chain
160 myosin light chain kinase
161 nerve endings
162 neuronal function
163 neurotransmitter synthesis
164 neutral protease
165 nonmuscle cells
166 nucleotide level
167 pathway
168 phenoxybenzamine
169 phospholipids
170 phosphorylase
171 phosphorylase kinase
172 phosphorylation
173 phosphorylation system
174 physico-chemical characteristics
175 physiological effects
176 physiological processes
177 platelets
178 possibility
179 presence
180 presence of cAMP
181 process
182 proenzyme
183 propranolol
184 protease
185 protein
186 protein I
187 protein kinase
188 protein kinase activators
189 protein phosphorylation
190 protein phosphorylation systems
191 proteolysis
192 pyruvate kinase
193 rat liver
194 rat tissues
195 recent years
196 receptor antagonist
197 receptors
198 redistribution
199 regulation
200 related proteins
201 release
202 release process
203 response
204 review
205 role
206 second messenger
207 second messenger systems
208 sensitivity
209 sites
210 skeletal muscle
211 slices
212 smallest active form
213 smooth muscle
214 species
215 specific array
216 specific effects
217 specificity
218 state
219 state of phosphorylation
220 stimulation
221 stimuli
222 stores
223 strong evidence
224 study
225 substrate
226 substrate proteins
227 subunits
228 synaptosomes
229 synthase
230 synthesis
231 system
232 tension development
233 tetrameric enzyme
234 tissue
235 ubiquitous calcium-binding protein
236 universal biochemical mechanism
237 variety
238 vasopressin
239 vivo
240 vivo studies
241 widespread distribution
242 years
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