Physiology Lecture #2 [Receptors & G-protein Coupled Receptors]

Effects of Receptors

1. Respond to specific molecules in the environment (Hormones, NT, Metabolic signals)

2. Cause the cell to respond to the signals

- Alter cell excitability (increase or decrease)

- Cause cell to secrete specific substance

- Change cellular transcription

Types of Cellular Receptors

1. Channel Receptors

2. GPCR

3. Tyrosine Kinase Receptors

4. Nuclear Receptors

Channels work by

Opening pathway for ions to cross the membrane. They excite or inhibit cells based on the ions they allow through

G Protein Coupled Receptors work by

Changing the biochemical status of the cell with many possible effects downstream

Tryosine Kinase Receptors (RTK) activation mechanism

1. Dimerize upon binding ligand

2. Autophosphorylate and activate or inhibit cell enzymes

Main function of RTK

Phosphorylation

Nuclear Receptors Mechanism

- Bind the ligand and bind to specific DNA sequences in nucleus

- Change Gene transcription

Nuclear Receptors Ligands are

Hydrophobic

What is most diverse group of receptors and can be found throughout the body

GPCRs

How many membrane spanning regions in a GPCR

7

Variable length Extracellular Terminal of GPCRs

NH3+ terminal

Long intracellular Terminal of GPCRs

COO- terminal

__ intracellular loops

3 (intra)

__extracellular loops

3 (extra)

The ___ intracellular loop and ____ terminal interact with the G protein

3rd, Carboxy

Ligand binding for GPCR is

Variable

All G proteins are ____ proteins with alpha, beta, and gamma subunits

hererotrimeric

____ are activated by GPCRs

G-Proteins

G-proteins are inactivated by

RGS

If the alpha subunit is bound to GDP the G protein is

Inactive

If the alpha subunit is bound to GTP the G protein is

Active

The alpha subunit has a _____ activity

GTPase

Upon activation the alpha and Beta/gamma dimer

Separate

Ways to "switch off" the GPCR

1. RGS: Exchanges GTP/GDP on alpha unit of G protein

2. Agonist dissociates from GPCR

3. GPCR-agonist complex gets internalized

The Gs type of G protein ____ the production of ___

Stimulates, cAMP

Hormone systems working through Gs type

Epinephine (adrenaline)

Antidiuretic Hormone

Thyroid Stimulating Hormone

Activation of Gi type G proteins leads to the ___ of ____ and thus a reduction of cAMP

Inhibition,Adenylyl cyclase, reduction

Systems working through Gi

Somatosatin

Cannabinoids

Muscarinic (ACh)

Stimulation of Gq type G proteins leads to increased levels of ____

Inositol triphosphate (IP3) and Diacylglyceride (DAG)

IP3 leads to the release of internal stores of

Calcium

DAG leads to the activation of

Protein Kinase C (PKC)

Systems utilizing Gq pathways

Alpha-1 adrenergic receptors in smooth muscle

Histamine 1 receptors in epithelial cells

Binds at the same site as agonist (when low physiological level of endogenous agonists)

Orthosteric agonist (OA)

Binds at a different site from agonist but facilitates agonist binding/GPCR activation (when GPCR not as efficient)

Allosteric agonist (AA)

Reduces basal levels of GPCR activation (hyperactive GPCRs)

Inverse agonist

Binds at the same site as agonist but does not activate GPCR and prevents agonist binding (hyperactive GPCRs or excess of endogenous agonist)

Competitive antagonist (CAnt)

Binds at a different site from agonist but reduces agonist binding/GPCR activation (for hyperactive GPCRs)

Allosteric antagonist (AAnt)