Phospholipase C

Cleavage sites of phospholipases. Phospholipase C enzymes cut just before the phosphate attached to the R₃ moiety.

Phospholipase C (PLC) is a class of enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role in eukaryotic cell physiology, in particular signal transduction pathways. Thirteen kinds of mammalian phospholipase C are classified into six isotypes (β, γ, δ, ε, ζ, η) according to structure.

Mammalian variants

beta: PLCB1, PLCB2, PLCB3, PLCB4
gamma: PLCG1, PLCG2
delta: PLCD1, PLCD3, PLCD4
epsilon: PLCE1
eta: PLCH1, PLCH2
zeta: PLCZ1
phospholipase C-like: PLCL1, PLCL2

Activation

Receptors that activate this pathway are mainly G protein-coupled receptors coupled to the G_αq subunit, including:

5-HT₂ serotonergic receptors
α₁ (Alpha-1) adrenergic receptors^[1]
Calcitonin receptors
H₁ histamine receptors
Metabotropic glutamate receptors, Group I
M₁, M₃, and M₅ muscarinic receptors
Thyroid-Releasing Hormone receptor in anterior pituitary gland

Other, minor, activators than G_αq are:

MAP kinase. Activators of this pathway include PDGF and FGF.^[1]
βγ-complex of heterotrimeric G-proteins, as in a minor pathway of growth hormone release by growth hormone-releasing hormone.^[2]

Effects

PLC mediated cleavage of PIP2 to DAG and IP3

PLC cleaves the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP₂) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃). DAG remains bound to the membrane, and IP₃ is released as a soluble structure into the cytosol. IP₃ then diffuses through the cytosol to bind to IP₃ receptors, particularly calcium channels in the smooth endoplasmic reticulum (ER). This causes the cytosolic concentration of calcium to increase, causing a cascade of intracellular changes and activity.^[3] In addition, calcium and DAG together work to activate protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity.^[3] End-effects include taste, tumor promotion, etc.^[3]

Further information: Calcium function in vertebrates, Function of protein kinase C

Additionally, phospholipase c plays an important role in the inflammation pathway. The binding of agonists such as thrombin, epinephrine, or collagen, to platelet surface receptors can trigger the activation of phospholipase C to catalyze the release of arachidonic acid from two major membrane phospholipids, phosphatidylinositol and phosphatidylcholine. Arachadonic acid can then go on into the cyclooxygenase pathway (producing prostoglandins (PGE1, PGE2, PGF2), prostacyclins (PGI2), or thromboxanes (TXA2)), and the lipoxygenase pathway (producing leukotrienes (LTB4, LTC4, LTD4, LTE4)).

In other organisms

Other phospholipase C enzymes have been identified in bacteria and in trypanosomes, each with its own EC number

Phosphoinositide phospholipase C EC 3.1.4.11 The main form found in eukaryotes, especially mammals.
Zinc-dependent phospholipase C family of bacterial enzymes EC 3.1.4.3 that includes the alpha toxins of C. perfringens (also known as lecithinase), P. aeruginosa, and S. aureus.
Phosphatidylinositol diacylglycerol-lyase EC 4.6.1.13 Another related bacterial enzyme
Glycosylphosphatidylinositol diacylglycerol-lyase EC 4.6.1.14 A trypanosomal enzyme.

References

1 2 Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN 1-4160-2328-3. Page 104
↑ GeneGlobe -> GHRH Signaling Retrieved on May 31, 2009
1 2 3 Alberts B, Lewis J, Raff M, Roberts K, Walter P (2002). Molecular biology of the cell (4th ed.). New York: Garland Science. ISBN 0-8153-3218-1.

Intracellular signaling peptides and proteins

MAP

see MAP kinase pathway

Calcium

G protein

Heterotrimeric

cAMP:	Heterotrimeric G protein Gs/Gi Adenylate cyclase cAMP 3',5'-cyclic-AMP phosphodiesterase Protein kinase A

cGMP:	Transducin Guanylate cyclase cGMP 3',5'-cyclic-GMP phosphodiesterase Protein kinase G

G alpha subunit G_α GNAO1 GNAI1 GNAI2 GNAI3 GNAT1 GNAT2 GNAT3 GNAZ GNAS GNAL GNAQ GNA11 GNA12 GNA13 GNA14 GNA15/GNA16

G beta-gamma complex G_β GNB1 GNB2 GNB3 GNB4 GNB5 G_γ GNGT1 GNGT2 GNG2 GNG3 GNG4 GNG5 GNG7 GNG8 GNG10 GNG11 GNG12 GNG13 BSCL2

G protein-coupled receptor kinase AMP-activated protein kinase

Monomeric

Cyclin

Lipid

Other protein kinase

Serine/threonine:	Casein kinase 1 2 eIF-2 kinase EIF2AK3 Glycogen synthase kinase GSK1 GSK2 GSK-3 GSK3A GSK3B IκB kinase CHUK IKK2 IKBKG Interleukin-1 receptor-associated kinase IRAK1 IRAK2 IRAK3 IRAK4 Lim kinase LIMK1 LIMK2 p21-activated kinases PAK1 PAK2 PAK3 PAK4 Rho-associated protein kinase ROCK1 ROCK2 Ribosomal s6 kinase RPS6KA1

Tyrosine:	ZAP70 Focal adhesion protein-tyrosine kinase PTK2 PTK2B BTK

both	Dual-specificity kinase

Other protein phosphatase

Serine/threonine:	Protein phosphatase 2

Tyrosine:	protein tyrosine phosphatase: Receptor-like protein tyrosine phosphatase Sh2 domain-containing protein tyrosine phosphatase

both:	Dual-specificity phosphatase

Apoptosis

see apoptosis signaling pathway

GTP-binding protein regulators

see GTP-binding protein regulators

Other

see also deficiencies of intracellular signaling peptides and proteins

Hydrolase: esterases (EC 3.1)

3.1.1: Carboxylic
ester hydrolases

Lipase

Phospholipase
- A1
- A2
- B

3.1.2: Thioesterase

3.1.3: Phosphatase

3.1.4: Phosphodiesterase

3.1.6: Sulfatase

Nuclease (includes
deoxyribonuclease and
ribonuclease)

3.1.11-16: Exonuclease

Exodeoxyribonuclease	RecBCD

Exoribonuclease	Oligonucleotidase

3.1.21-31: Endonuclease

Endodeoxyribonuclease	Deoxyribonuclease I Deoxyribonuclease II Deoxyribonuclease IV Restriction enzyme UvrABC endonuclease

Endoribonuclease	RNase III RNase H 1 2A 2B 2C RNase P RNase A 1 2 3 4/5 RNase T1 RNA-induced silencing complex

either deoxy- or ribo-	Aspergillus nuclease S1 Micrococcal nuclease

Proteins: enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

Metabolism: lipid metabolism - eicosanoid metabolism enzymes

Precursor	Phospholipase A2 Phospholipase C Diacylglycerol lipase

Prostanoids	Cyclooxygenase PTGS1 PTGS2 PGD2 synthase PGE synthase Prostaglandin-E2 9-reductase PGI2 synthase TXA synthase

Leukotrienes	5-Lipoxygenase activating protein/Arachidonate 5-lipoxygenase LTA4 hydrolase (B4 synthesis) LTC4 synthase Gamma-glutamyl transpeptidase LTD4 hydrolase

Ungrouped	HPGD

Anabolism

to diacylglycerol: Acyltransferase Phosphatidate phosphatase 2C

Choline kinase CHKA CHKB Choline-phosphate cytidylyltransferase

phosphatidylinositol glycan anchor biosynthesis: PIGA PIGB PIGC PIGF PIGG PIGH PIGK PIGL PIGM PIGN PIGO PIGP PIGQ PIGS PIGT PIGU PIGV PIGW PIGX PIGY PIGZ

cardiolipin: Tafazzin

Catabolism

Phospholipase C

Diacylglycerol kinase DGKA DGKB DGKD DGKE DGKG DGKH DGKI DGKK DGKQ DGKZ

Phosphoric monoester hydrolases Inositol-phosphate phosphatase

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