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Intercelluler Communication
All cells detect and respond to environmental stimuli Intracelluler communication : - endocrine - nervous - immune Endocrine glands secrete hormones
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Long Distance Communication: Hormones

Signal Chemicals Made in endocrine cells Transported via blood Receptors on target cells
Long distance cell-to-cell communication BIOCHEMISTRY MEDICAL FACULTY USU

Paracrines and Autocrines

Local communication Signal chemicals diffuse to target Example: Cytokines
Autocrinereceptor Autocrine on same cell Paracrine Paracrine neighboring cells
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Direct and local cell-to-cell communication

Signal Pathways
Signal molecule (ligand) Receptor Intracellular signal Target protein Response

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Signal pathways

Hormone Receptors
Receptors : a protein that binds a hormone with high affinity All receptors are proteins Have at least two functional domains : 1. A recognition domain binds the hormone ligand 2. A second region generates a signal that couples hormone recognition to some intracellular function
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Hormone Receptors
Only the target cells for a certain hormone have receptors for that hormone Receptor density of target cells: 2000-100,000 2000receptors/hormone
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Receptor locations Cytosolic or Nuclear

Lipophilic ligand enters cell Often activates gene Slower response

Cell membrane
Lipophobic ligand can't enter cell Outer surface receptor Fast response

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Hormone - Target Cell Specificity

Receptors are dynamic structures: they can respond to rising levels of hormones by increasing in number (up-regulation) up-regulation) Respond to prolonged exposure to high hormone concentrations by reducing the number of receptors (down(downregulation) regulation) BIOCHEMISTRY
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Receptors Intracelluler
Hormones can diffuse through the lipid bilayer of the plasma membrane receptors intracelluler The lipid soluble hormone diffuses into the cell Binds to the receptor conformational change Binds to specific DNA sequences response elements (HRE)
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Receptors Intracelluler
These DNA sequences are in the regulatory regions of genes. Stimulating the transcription of messenger RNA. The messenger RNA travels to the cytoplasm translated into protein

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Mechanism of lipid soluble hormone action

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Action of Steroid Hormones

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Receptors on The Plasma Membrane

Receptors for the water soluble hormones Couple to various second messenger systems mediate the action of the hormone in the target cell Second messenger : cAMP cGMP Ca 2+ Phosphoinositide/Diacylglycerol(DAG) Protein Kinase

Membrane-bound Hormone Receptors

Second Messenger Systems

1.Cyclic 1. Cyclic AMP (cAMP)
Polypeptide or glycoprotein hormones bind to receptor protein dissociation of a subunit of G-protein GThe G-protein is trimer (, and subunit) G( The subunit: - bound to GDP in the native G protein

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Second Messenger Systems

1. Cyclic AMP (cAMP) - the hormone receptor complex exchange of GTP - dissociates from G - stimulates the adenylate cyclase - ATP is converted to cAMP ATP cAMP + PPi
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Activation of adenylate cyclase by binding of a hormone to its receptor

Second Messenger Systems

1. Cyclic AMP (cAMP)
- The generation of

cAMP usually activates protein kinase A (PKA) - This results in activation of cAMPdependent protein kinase (PKA) with consequent Activation of PKA phosphorylation of target proteins BIOCHEMISTRY
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1. Cyclic AMP (cAMP) - cAMP hydrolyzed by cAMP phosphodiesterase to 5-AMP 5- phosphodiesterase inhibited by methylxanthine derivatives

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Second Messenger Systems

1. Cyclic AMP (cAMP)
Cholera toxin -block Gs, hydrolysis of GTP to GDP -severe diarrhea Pertussis toxin -block Gi, exchanging GDP for GTP -whooping cough

Cholera toxin Pertussis toxin

Action of Vasopressin/VP in Distal Kidney Tubules

Second Messenger Systems

2. Cyclic GMP (cGMP)

Membrane bound Guanylate cyclase is an integral part of the receptor and hence is structurally similar to tyrosine specific protein kinases GTP Guanylate cyclase cGMP Protein kinase G
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Second Messenger Systems

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Second Messenger Systems

2. Cyclic GMP (CGMP) Atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) activate guanylate cyclase Increase blood volume : release ANF from heart atrial cells. Effects : lowering of BP via vasodilation and diuresis ANF cGMP increase renal excretion of Na+ and water
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Second Messenger Systems

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Second Messenger Systems

2. Cyclic GMP (CGMP) Nitric oxide (NO): stimulate synthesis of cGMP The resultant rise in cGMP muscle relaxation, through activation of PKG, which phosphorylates myosin lightlightchain kinase and renders it inactive used to treat patients with angina
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Second Messenger Systems

3. Calcium Many cells respond to extracellular stimuli by altering their intracellular calcium concentration interaction with concentration calmodulin Calcium levels controlled by phosphoinositide system Calcium ion may be more of a third messenger
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Second Messenger Systems

4. Phosphoinositide/Diacylglycerol (DAG) Phosphoinositide/ Cytosolic calcium ion levels increased by release from intracellular calcium stores Controlled by the phosphoinositide system Hormonal stimulus splits phospholipid PIP2 into IP3 and DAG by phospholipase C

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Phosphoinositide system - Ca2+

IP3 diffuses through cytoplasm to ER. Binding of IP3 to receptor protein in ER causes Ca2+ channels to open. Ca2+ diffuses into the cytoplasm. Ca2+ binds to calmodulin. Calmodulin activates specific protein kinase enzymes
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Phosphoinositide system - Ca2+

DAG activates protein kinase C Alters the metabolism of the cell, producing the hormones effects The conversion of inositol phosphate to inositol is inhibited by lithium ion treatment of manic-deppressive manic-

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Phosphoinositide system - Ca2+

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Second Messenger Systems

Second messenger systems a specific protein kinase enzyme The generation of second messengers and activation of specific protein kinase results in changes in the activity of the target cell which characterizes the response that the hormone evokes Certain receptors have intrinsic kinase activity These include receptors for growth factors, insulin, IGF,EGF, etc

PROTEIN TYROSINE KINASE RECEPTORS

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Action of Insulin

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EICOSANOIDS HORMONE
Roles in inflammation, fever, regulation of blood pressure, blood clotting, control of reproductive processes & tissue growth, sleep/wake cycle regulation Most affect other cells by interacting with plasma membrane G-protein coupled Greceptors.

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Prostaglandins
Depending on the cell type, the activated G-protein may stimulate or inhibit formation of cAMP (PGE2 and PGI2) by stimulate or inhibit adenylate cyclase PGF PGF2 can be activate a phosphatidylinositol signal pathway leading to intracellular Ca++ release

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Prostaglandins
Different prostaglandins may exert antagonistic effects in some tissues. Immune system: Promote inflammatory process. Reproductive system: Play role in ovulation. Digestive system: Inhibit gastric secretion Respiratory system: May bronchoconstrict or bronchodilate. Circulatory system: Vasoconstrictors or vasodilators. Urinary system: BIOCHEMISTRY Vasodilation MEDICAL FACULTY USU

REFERENCES
Devlin T M, PhD. Text Book of Biochemistry with Clinical Correlations 5thed. Wiley-Liss, New York. Wiley2002 : 906-952, 982-983 906982McKee Trudy, McKee James R. The molecular basis of Life. 3rded. McGraw-Hill. Americas, New McGrawYork. 2003 : 541-559 541Murray R K, et al. Harpers Biochemistry 26thed. Appleton & Lange. America 2003: 434-473 434Raff A, et al. Moleculer Biology of The Cell. 4thed. Garland Science. New York. 2002: 832-892 832Stryer L. Biokimia. Edisi 4. EGC, Jakarta. 2000.: 340340-358
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