Pharmacodynamics Signaling Mechanism Flashcards
SIGNALING MECHANISMS AND DRUG ACTION
● Five basic mechanisms of transmembrane signaling
● Binding of the drug to the receptor would then cause change in the receptor. And some of these receptors would further activate signaling mechanisms (second messengers).
A lipid-soluble chemical signal
crosses the plasma membrane and acts on an intracellular receptor (which may be an enzyme or a regulator of gene transcription)
the signal binds to the extracellular domain of a transmembrane protein, thereby
activating an enzymatic activity of its cytoplasmic domain;
the signal binds to the extracellular domain of a transmembrane receptor
bound to a separate protein tyrosine kinase, which it activates
the signal binds to a cell-surface receptor linked to an effector enzyme
G protein
INTRACELLULAR RECEPTORS FOR LIPID SOLUBLE AGENTS
● The mechanism used by hormones that act by regulating gene expression has two therapeutically important consequences:
- All of these hormones produce their effects after a characteristic lag period of 30 minutes to several hours 2. The effects of these agents can persist for hours or days after the agonist concentration has been reduced to zero.
Ligand binding to the receptor which is located intracellularly-causes gene transcription by response element present in the nucleus - gene transcription producing biologic effect
e.g. - steroids, glucocorticoids, vitamin D, nitric oxide, a few other highly membrane permeable agents cross the membrane and activate intracellular receptors
. LIGAND REGULATED TRANSMEMBRANE ENZYMES INCLUDING RECEPTOR TYROSINE KINASE
Mechanism of activation of the epidermal growth factor (EGF) receptor, a representative tyrosine kinase
The receptor polypeptide has extracellular & cytoplasmic domains, depicted above and below the plasma membrane. Upon binding of EGF (circle), the receptor converts from its inactive monomeric site (left) to an active dimeric state (right), in which two receptor polypeptides bind noncovalently. The cytoplasmic domains become phosphorylate (P) on specific tyrosine residues (Y), and their enzymatic activities are activated, catalyzing phosphorylation of substrate protein (S).
These receptors mediate in the 1st steps in signaling by insulin and growth factors including epidermal GF
Binding of the ligand causes conformational changes so that tyrosine kinase domain becomes activated → phosphorylation of tissue specific substrate proteins. e.g. insulin (binding of the insulin to the insulin receptor would activate tyrosine kinase causing phosphorylation of tissue specific substrate protein), EDF and similar agents that bind to extracellular domain of molecules that incorporate tyrosine kinase activity.
CYTOKINE RECEPTORS
Cytokine Receptors, like receptor tyrosine kinases, have extracellular and intracellular and form dimers. However, after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK) are activated, resulting in phosphorylation of signal transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the nucleus, where they regulate transcription
CYTOKINE RECEPTORS include which hormone receptors
erythropoetin and interferon
JAK-STAT
Jak phosphorylate signal transduces and activation of transcription(stat) molecules. Stat dimerizes then dissociates → gene transcription.
LIGAND AND VOLTAGE GATED CHANNELS
1
G PROTEIN AND SECOND MESSENGERS
G stimulatory (Gs)
It stimulates the production of cyclic AMP - so binding of the ligand to the receptor would stimulate the adenyl cyclase via DS, So GDP bound to the alpha subunit of Gprotein coupled receptor to convert ATP to cyclic
Increasing cyclic AMP produces the biologic effect
G inhibitory (Gi) -
It inhibits the production of your cyclic AMP.
● (Gq) - Involves the activation of phospholipase C, inducing formation of inositol-trisphosphate and diacylglycerol - Diacylglycerol would activate protein kinase C which leads to protein phosphorylation - while your IP3 which is water soluble mobilizes the calcium producing biologic effect.
What is the advantage of the second messenger?
They can amplify the signals. If a drug binds to the receptor (1 sec only) but with the second messenger it can prolong the effect of the binding of the drug to the receptor.
G protein effector table
CYCLIC ADENOSINE MONOPHOSPHATE (cAMP)
● Binding of agonists linked to G1 CHON decreases cAMP production.
● Example: Alpha adrenoceptor, Ach, D
G. CALCIUM AND PHOSPHOINOSITIDES
● Other receptor system are coupled via GTP binding CHON which activates phospholipase C
● Activation of this enzyme releases the second messenger inositol triPO4(IP3) and DAG
● The IP3 induces release of Ca for sarcoplasmic reticulum which together with DAG→ activate CHON kinase C → phosphorylate a set of tissue substrate.
● Example: Ach, NE
● Five basic mechanisms of transmembrane signaling
● Binding of the drug to the receptor would then cause change in the receptor. And some of these receptors would further activate signaling mechanisms (second messengers)
TOLERANCE
Responsiveness decreases as a consequence of continuous drug administration
TACHYPHYLAXIS
Responsiveness diminishes rapidly after administration of a drug
ALTERATION IN CONCENTRATION OF DRUG THAT REACHES THE RECEPTOR
● Age ● Weight ● Sex ● Disease state ● Liver and kidney function
VARIATION IN CONCENTRATION OF ENDOGENOUS RECEPTOR LIGAND
Propranolol in patient with pheochromocytoma
ALTERATIONS IN NUMBER OR FUNCTION OF RECEPTORS
Clonidine (alpha 2 agonist) → HPN crisis → downregulates receptor
Continuous administration of agonist
DOWNREGULATES the receptor
Continuous administration of antagonist
UPREGULATES the receptor
