MR S7 - Signal Transduction in Biological Membranes Flashcards Preview

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Flashcards in MR S7 - Signal Transduction in Biological Membranes Deck (29)
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0

How do GPCRs act?

By altering the activity of effectors via the activation of one or more guanine nucleotide binding proteins (G proteins)

1

Describe the structure of G proteins

Heterotrimeric (made up of three different or distinct subunits)
The b and g subunits bind tightly and act as a single unit
The a subunit has a guanine nucleotide binding site where GTP binds and is slowly hydrolysed to GDP

2

Describe GPCR structure when receptor is not activated

G protein is usually on the inner face of the membrane
Subunit a has a GDP bound

3

Describe the sequence of events after an agonist binds to a GPCR

Receptor has high affinity for GDP-bound a subunit
Protein-protein interaction occurs
Results in the release of GDP and the binding of GTP
Affinity for a and b-g subunits is reduced so are released
Subunits interact with effectors

4

How does interaction of G protein subunits stop?

Intrinsic GTPase activity of the a subunit hydrolyses GTP to GDP
The affinity of the a and b-g subunits increases
ABG heterotrimer reforms and awaits deactivation by agonist-bound receptor

5

Describe the action of Gs

β receptor activated by adrenaline agonist
Gs is the a subunit of the G protein
Gs stimulates adenylyl cyclase to increase cAMP production

6

Describe the action of Gi

α2 receptor activated by binding of adrenaline agonist or M2 receptor activated by binding of acetylcholine agonist
Gi is the a subunit of the G protein involved
Gi inhibits adenylyl cyclase to reduce cAMP production

7

Describe the action of Gq

α1 receptor activated by binding of adrenaline agonist or M1 or M3 receptor activated by binding of acetylcholine agonist
Gq

8

Describe the action of Gt

In retinal rod cells, the protein rhodopsin detects light and activates a G protein
Gt is the a subunit of the G protein involved
Gt activates phosphodiesterase which hydrolyses cyclic GMP to 5'-GMP

9

Discuss G protein diversity

Human genome codes for 20a, 5b and 12+g subunits
Therefore 1000+ ABG combinations
800+ receptor types to interact with different Ga subunits
Can activate 10+ enzymes/ion channels

10

Discuss the specificity of G protein action

An extracellular signal can activate 1 or many G proteins and effectors to bring about a specific cellular response

11

Describe the action of the cholera toxin

Capable of ADP-ribosylating specific G proteins
CTx eliminates the GTPase activity of the Gs a subunit, which leads to it becoming permanently activated

12

Describe the action of the Pertussis toxin

Capable of ADP-ribosylating specific G proteins
PTx interferes with the GDP/GTP exchange on the Gi a subunit, which leads to it's permanent inactivation

13

Name some diseases caused by mutations to GPCRs

Retinis pigmentosa
Nephrogenic Diabetes Isipitus
Familial Male Precocious Puberty

14

Describe Retinis pigmentosa

Can be caused by a loss-of-function mutation in the gene coding for Rhodopsin

15

Describe Nephrogenic diabetes insipidus

Can be caused by a loss-of-function mutation to the V2 vasopressin receptor

16

Describe familial male precocious puberty

Caused by a gain-of-function mutation to the gene coding for the lute nosing hormone receptor
Causes receptor to be active without ligand binding

17

Describe adenylyl cyclase

Integral plasma membrane protein
Can be activated (via Gs) or inhibited (via Gi) by activation of various receptors
Hydrolyses cellular ATP to cAMP

18

Describe the action of cAMP

Interacts with a specific protein kinase: cyclic AMP dependent protein kinase (aka PKA)

19

Describe the action of PKA

Phosphorylates a variety of proteins within the cell to affect activity

20

Describe phospholipase C

An enzyme which hydrolyses the membrane phospholipid PIP2 to IP3
Activated by Gq

21

Describe the action of IP3

Interacts with specific intracellular receptors on the endoplasmic reticulum to allow Ca to leave the lumen of the ER and enter the cytoplasm

22

Describe cyclic GMP phosphodiesterase

Specialised mechanism found in the photoreceptive cells of the retina
Regulates the breakdown of cyclic GMP phosphodiesterase by Gt

23

How is a GPCR deactivated?

After receptor interaction with the G protein, the agonist binding is weakened and receptor-agonist dissociation is likely
Whilst activated, the receptor-agonist is vulnerable to a variety of protein kinases which prevent it activating more G proteins
Cellular factors can influence the GTPase activity of the a subunit
In the cell, basal rates are favoured for enzymes so there are many highly active enzymes which metabolise second messengers
Enzyme cascades initiated by second messengers often act to oppose the second messengers

24

Describe regulation of chronotropy in the heart

The rate of SAN impulses can be affected by ACh release from parasympathetic nerves
Receptor type is M2, which increases the open probability of K+ channels via the Gi subunit
This causes hyperpolarisation, slowing the intrinsic firing rate and resulting in a negative chronotropic effect

25

Describe regulation of intropy of the heart

Sympathetic stimulation of the cardiac ventricles (and circulating adrenaline) can influence intropy
Activation of

26

What is intropy?

The force of contraction of the cardiac ventricles

27

Describe arteriolar vasoconstriction

Sympathetic release of noradrenaline acts on α1 adrenoceptors to stimulate phospholipase c -> IP3 production via Gq
The IP3 causes Ca release into cell from ER and initiates contractile response

28

Describe modulation of neurotransmitter release

Presynaptic GPCRs can influence neurotransmitter release
Presynaptic m-opioid receptors can be stimulated by indigenous opioids and by analgesics eg morphine to couple to Gi a subunits
The Gbg subunits are liberated from the heterotrimer and interact with VOCCs to reduce Ca entry into cell, thus reducing neurotransmitter release