Home > Anatomy, Biology, Chemistry, pharmacology > Introduction to Pharmacology: GPCRs

Introduction to Pharmacology: GPCRs

Overview

This is a 62 minute lecture that had no quiz.  She just threw this in a few weeks back.  I think it’s an important topic because of how ubiquitous the G protein receptor is.

https://class.coursera.org/pharm101-2012-001/lecture/index#./12

Details

5 Transmembrane Signaling Mechanisms

1) A lipid soluble chemical signal crosses the plasma membrane and acts on an intracellular receptor.

2) Signal binds to the EC domain of the receptor, activating the enzymatic activity of the cytoplasmic domain of the receptor

3) Signal binds to the EC domain of the receptor bound to a tyrosine kinase which it activates

4) Signal binds and directly regulates opening of an ion channel

5) The signal binds to a cell surface receptor linked to an effector enzyme by a G protein.

GPCR – G Protein Coupled Receptor

Found in virtually every human cell.

40% of drugs clinically used target GPCRs.

The signal binds to a cell surface receptor link to an effector enzyme by a G protein.

They work by increasing the concentration of intracellular concentration of secondary messengers such as cAMP, calcium or phosphoinositides.

The GPCR traverses the phospholipid bilayer.  There are 7 transmembrane spanning domains.  There is the extracellular domain and the intracellular domain.

Has 3 subunits – alpha, beta, and gamma.  Heterotrimeric configuration.  Regulated by factors influencing GTP/GDP or GTP hydrolysis.  Activate or inhibit effectors in response to agonists.

Mechanism of Action

1) Extracellular ligand binds to a cell surface receptor.

2) Receptor trigger activation of a G protein located on the cytoplasmic face of the plasma membrane.  Activation involves dissociation of the subunits.

3) Actived G protein changes the activity of an effector element.  This element changes the concentration of the intracellular secondary messenger – cAMP, Ca2+.

The G receptor is seperate from the G protein, but they are coupled.

A Few G Proteins…

Gs  – Adenylyl cylase stimulates cAMP

Gi – Adenylel cyclase inhibition

Gq – Phospholipase C-B simulation Ca2+

Gs/Adenylyl cylase is stimulatory.  Epinephrine or adrenaline is a natural ligand/drug binds to the EC GPCR.  The Beta 1 adrenergic receptor.  Dissociation of the subunits.  The effector is adenylyl cylase.  Epinephrine leads to dilation of lung tissue, bronchiolar smooth muscle.

Histamine binds to the H1 receptor.  This leads to constriction.

Platelets are cell fragments.  They regulate how blood clots.  Regulated by two prostaglandings thromboxane and prostaglandin, TXA2, PGI2.  One promotes aggregation, one resists aggregation.  Aspirin creates an imbalance and “thins” the blood.

The relationship between many receptors, G proteins connected to different effectors is very complicated.

GPCR: Receptor Subtypes and Relevent Drug Development

A single agonist can often be recognized by a group of GPCRs.  These almost always are similar in sequence and are refered to as subtypes.

While subtypes of a receptor will recognize a common physiological agonist, subtle differences in structure and sometimes large differences in anatomic distribution provide unique pharmacological points of attack.

A single agonist can be recognized by a group of subtypes.

Subtypes:

Adenosine, a-adrenergic, b-adrenergic, dopaminergic, histamineergic, muscarinic, opoid, angiotensin, somatostatin, seratonergic.

For example, histaminergic has 3 subtypes: H1, H2, H3.

H1 is bronchiolar smooth muscle, H2 is vascular smooth muscle.

Epinephrine binds to two different subtypes like cardiac myocyte and bronchiolar smooth muscle.  These receptors are found in different concentrations in different tissues.

Physiologic Antagonism

An allergic reaction.  An antigenic challenge comes, activating the mast cell, that releases histamine.  The man takes an antihistamine to resist the symptoms.  There is no binding to H1, which hits bronchiolar smooth muscle, intense bronchoconstriction.  This response is amplified by leukotrienes, thromboxane, and prostaglandings.

You could try antihistamine.  Epinephrine will cause relaxation more quickly.  The beta 2 receptor is also on the bronchiolar smooth muscle tissue, so this will work.

Selectivity is needed to reduce side effects.  Some molecules will have a primary activity at one receptor subtype.

Modulation of Receptor Response

G protein mediated responses to drugs and endogenous ligands can change:

after reaching an initial high, the response can diminish over time

Referred to as desensitization and is achieved by phosphorylation of the receptor

Typically reversible following exposure to more agonist

Down Regulation

receptor heterodimerization leading to endocytosis of the receptor – throwing the receptor away because it is used up.

Desensitization

GPCR Desensitization

Mechanism involves phosphorylation of the serine residues of the GPCR carboxyl tail, by G protein coupled receptor kinases (GRKs).

This recruits B – arrestin

Presence of B arrestin decreases receptor ability to interact with G protein subunit.

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