Different Protein kinases and their importance

1. Presented by- Mukul Tambe.
M.pharm. Sem. I
Pharmacology
H.O.D.: Prof. B. Veersh.
Date of Submission:
PROTEIN KINASES
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2.  Phosphorylation of other proteins.
 Functional change of target proteins.
 500 types of PK Genomes.
 30% Can be modified by PKs.
 Also found in Bacterias and Plants.
INTRODUCTION:
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3.  Highly regulated activity due to profound
activity on cells.
 Turn “ON” and “OFF” by Activator Proteins
and Inhibitor Proteins.
 Auto phosphorylation / Cis- Phosphorylation.
REGULATION:
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4. 1 ACG kinase containing PKA, PKC and PKG.
2 CaM kinase containing the calcium/calmodulin-dependent protein
kinases.
3 CK1 containing the casein kinase 1 group.
4 CMGC containing CDK, MAPK, GSK3 and CLK kinases.
5 STE containing the homologs of yeast Sterile 7, Sterile 11,
and Sterile 20 kinases.
6 TK containing the tyrosine kinases
7 TKL containing the tyrosine-kinase like group of kinases.
P.K. GROUPS:
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5. PROTEIN KINASE A
ACTIVATION
Gs-α Subunit activation
Activation of adenylate cyclase
Increases cAMP
4 cAMP molecules are reqd. for
activation of single PKA
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6. SR.
NO.
CELL TYPE STIMULATOR
S
EFFECTS
1. Adipose Epinephrine:β-
adrenoceptor
Glucagon: Glucagon
receptor
Enhances Lipolysis by stimulating lipase
2. Skeletal Muscle Epinephrine:β-
adrenoceptor
Stimulate Glucogenolysis & Glycolysis
Inhibits gluconeogenesis
3. Cardiac Muscle Nor-Epinephrine:β-
adrenoceptor
Sequester Ca2+ in sarcoplasmic reticulum
Phosphorylates phospholamban
4. Neurons in Nucleus Dopamine: DA
Receptor
Activate Reward System
5. Thick ascending
limb cell
Vasopressin: V2
receptor
stimulate Na-K-2Cl symporter
FUNCTIONS:
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7. 6. Cortical collecting
tubule cell
Vasopressin: V2
receptor
Stimulate Epithelial sodium channel
7. Inner medullary
collecting duct cell
Vasopressin: V2
receptor
Stimulate urea transporter 1
Urea transporter 1 exocytosis
8. Proximal
convoluted tubule
PTH: PTH receptor
1
Inhibit NHE3: ↓H+ secretion
9. Juxtaglomerular
cell
Adrenergic
agonists: β-receptor
Agonists:
α2 receptor
Dopamine:
dopamine receptor
Glucagon: glucagon
receptor
Renin secretion
10. Principal
cells in kidney
Vasopressin: V2
receptor
Theophylline
Exocytosis of aquaporin 2 to apical membrane
Synthesis of aquaporin 2
FUNCTIONS: (CNTD..)
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8. 11. Hepatocyte Epinephrine: β-
adrenoceptor
Glucagon:
Glucagon
receptor
Stimulate glucogenolysis
Stimulate glycolysis
Inhibit glycogenesis
Inhibit gluconeogenesis
12. Smooth muscle
(Cardiovascula
r)
β2 adrenergic agonists: β-
2 adrenergic receptor
Histamine: Histamine H2
receptor
Prostacyclin: prostacyclin
receptor
Prostaglandin D2:
PGD2receptor
Prostaglandin E2:
PGE2receptor
VIP: VIP receptor
L-Arginine:
Imidazoline and α2 recept
or
Vasodilation
FUNCTIONS: (CNTD..)
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9. Feedback mechanism of Phosphodiesterase
Quick conversion of cAMP to AMP
Downregulation of PKA
INHIBITION:
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10. ACTIVATION
Gq-α Subunit activation
Activation Phospholipase C
IP3 and DAG
DAG With Ca++ Activates
PKC
PROTEIN KINASE C:
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11. FUNCTIONS:
SR.
NO.
CELL TYPE STIMULATOR
S
EFFECTS
1. Gastrointestinal tract
sphincters
Prostaglandin
F2α
:
Thromboxanes
Contraction
2. Smooth muscle cell
(vascular)
5-HT: 5-HT2A
receptor
Adrenoceptor:
α1 receptor
Vasoconstriction
3. Proximal convoluted
tubule cell
Angiotensin II:
AT1 receptor
Adrenoceptor
:α1 receptor
H+ secretion & Na+ reabsorption
Stimulate basolateral Na-K ATPase
4. Ependymal cells 5-HT:5-HT2C
receptor
↑cerebrospinal fluid secretion
5. Heart muscle β1 receptor Positive inotropic effect
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12. 6. Neurons in CNS 5-HT: 5-HT2A
receptor
Glutamate:
NMDA receptor
Neuronal excitation (5-HT)
Memory (glutamate)
7. Platelets 5-HT: 5-HT2A
receptor
Aggregation
8. Serous
cells (lacrimal
gland)
Acetylcholine: M
3 receptor
↑secretion
9. Serous
cells (salivary
gland)
Acetylcholine: M1
and M3 receptors
adrenergic agonist:
β1 receptor
↑secretion
Increase salivary potassium levels.
10. Parietal cells Acetylcholine: M
3 receptors
↑ gastric acid secretion
FUNCTIONS: (CNTD..)
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13.  Protein kinase C inhibitors, such as ruboxistaurin,
may potentially be beneficial in peripheral diabetic
nephropathy.
 Natural selective PKC inhibitor: Chelerythrine.
 Other naturally occurring PKCIs: Miyabenol
C, Myricitrin, Gossypol.
 Other PKCIs : Verbascoside, BIM-1.
 Bryostatin 1 can act as a PKC inhibitor; It was
investigated for cancer.
PKC INHIBITORS:
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14. ACTIVATION
Serine/Threonine-specific protein
kinase
Activated by cGMP
PROTEIN KINASE G:
Also called as
cGMP dependent
Protein kinase
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15.  Phosphorylation of no. of biologically important
targets.
 Regulation of:
 Smooth muscle relaxation.
 Platelets function.
 Sperm metabolism.
 Cell division.
 Nucleic acid synthesis.
FUNCTIONS:
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16.  PKG 1 & PKG 2: homodimers of two
identical subunits (~75 kDa and ~85 kDa, respectively)
 Each subunit is composed of three functional domains:
(1) an N-terminal domain that mediates homodimerization,
suppression of the kinase activity in the absence of cGMP, and
interactions with other proteins including protein substrates
(2) a regulatory domain that contains two non-identical cGMP-
binding sites
(3) a kinase domain that catalyzes the phosphate transfer
from ATP to the hydroxyl group of a serine/threonine side
chain of the target protein
GENES AND PROTEINS:
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17.  Smooth muscle cells
 Vascular smooth muscles
 Vascular endothelium
 Cardiomyocytes
 Renal cells
 Nervous system
 Renal cells
 Zona glomerulosa
 Intestinal mucosa
 Pancreatic duct
 Submandibular glands
 Several brain nuclei
PKG I PKG II
TISSUE DISTRIBUTION:
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18.  Cancerous colon cells stop producing PKG,
which apparently limits beta-catenin thus
allowing the VEGF enzyme to solicit
angiogenesis.
ROLE IN CANCER:
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19. 1. Casteel DE, Smith-Nguyen EV, Sankaran B, Roh SH, Pilz RB, Kim C
(October 2010). "A crystal structure of the cyclic GMP-dependent protein
kinase I{beta} dimerization/docking domain reveals molecular details of
isoform-specific anchorinG”
2. Kyle BD, Hurst S, Swayze RD, Sheng J, Braun AP (Feb 2013). "Specific
phosphorylation sites underlie the stimulation of a large conductance,
Ca(2+)-activated K(+) channel by cGMP-dependent protein kinase“
3. Lodish et al. 2016 Molecular cell biology, 8th Ed. Ch. 15.5. pg. 701. W.H.
Freeman and Company. ISBN 978-1-4641-8339-3
4. Voet, Voet & Pratt (2006). Fundamentals of Biochemistry. Wiley. Pg 492
5. Walter F. Boron (2005). Medical Physiology: A Cellular And Molecular
Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3. Page 787
REFERENCES:
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