2015-11-22

Cell Biology
Lecture 223.21: G-Linked Protein Receptors

Cell Signaling

2015-11-22

G-Linked Protein Receptors

Largest family of cell surface receptors
7-pass transmembrane protein
numbers present vary by organism
(700 known in humans)
Each type mediates responses to different ligands
proteins,
modified amino acids,
fatty acids
Same ligand can activate
several G protein
receptors
Each G-protein receptor
interacts with a specific
G-Protein

Cell Signaling - GTP-binding protein

To turn on proteins signalling activity:
1. release bound GDP
2. bind GTP
(nucleotide exchange)
Resultant signal may be:
1. stimulatory (Gs) or
2. inhibitory (Gi)
To turn off signaling activity:
hydrolysis of GTP
by intrinsic GTPase
causes inactivation

2015-11-22

G-Linked Protein Receptors & G-proteins

G-protein:
at least 20 types in humans
trimeric complex
(for specifics of G-protein attachment to cell membrane,
review Lecture 13: Membrane proteins)

G-protein activation
To turn on G-protein activity:
1. Receptor binds signal
molecule
2. G-protein
a. binds activated receptor
b. releases bound GDP
c. bind GTP
Depending on the G-protein
the resultant activity may be:
1. stimulatory (Gs) or
2. inhibitory (Gi)
Resultant activity may be from
1. subunit
2. complex
3a. both and , together
3b. both and , separately

2015-11-22

G-protein: complex
Some G proteins directly regulate ion channels
e.g.

complex activates target

here, a K+ channel

To turn off signalling activity:

1. hydrolysis of GTP
by GTPase activity
intrinsic to subunit
causes inactivation of
2. reassociation of (inactive)
with inactivates

G-protein: subunit
subunit activates target
here, i.e., an enzyme
(adenylyl cyclase)
To turn off signalling activity:
1. hydrolysis of GTP
by GTPase activity
intrinsic to subunit
causes inactivation
(usually within seconds)
2. reassociation of (inactive)
with inactivates

2015-11-22

G-protein: subunit

Caffeine Inhibits
RAPID

G-protein & Receptors: Adrenaline case study

The same extracellular signal
(e.g. adrenaline, the fight or flight hormone) can
initiate different responses in
different cell types:

1. Heart cell
increased [cAMP] increased heart rate
2. Muscle cell
increased [cAMP] increased glycogen breakdown

2015-11-22

G-protein & Receptors: Adrenaline case study

The same extracellular signal
(e.g. adrenaline, the fight or flight hormone) can
initiate opposite responses mediated by
different G-proteins and receptors:
1. adrenaline binds to -adrenergic receptor
activates stimulatory G-protein (Gs)
Gs turn adenylate cyclase ON
result: increased cAMP concentration
2. adrenaline binds to 2-adrenergic receptor
activates inhibitory G-protein (Gi)
Gi turns adenylate cyclase OFF
result: decreased cAMP concentration
Note: - the and subunits of Gs and Gi are identical-they differ
only in the subunit

How does cAMP influence

downstream events in the cell?

Protein Kinase A (PKA): regulatory + enzymatic subunits

regulatory subunits inhibit kinase activity
binding of cAMP dissociates regulatory subunits
dissociation activates kinase activity
enzyme phosphorylates its target proteins to
cause different effects

2015-11-22

G-Linked Protein Receptors

Adrenalin rapid response
e.g. 1 Adrenaline-mediated
cAMP response
in skeletal muscle
PKA activation result:
1. glycogen breakdown
(power boost)
2. stop glycogen synthesis
(not shown)
e.g. 2 Adrenaline-mediated
cAMP response
in heart muscle
result:
increase heart rate

G-Linked Protein Receptors

2015-11-22

G-Linked Protein Receptors

G-Linked Protein Receptors and cAMP

Adrenalin slow response
Adrenaline-mediated cAMP
response in hypothalamus
(endocrine cells)
PKA activation result:
1. Activate transcriptional
regulator
2. Turn on subset of genes,
including somatostatin
(which controls
hormone release)

2015-11-22

G-Linked Protein Receptors

Cell Biology
Lecture 223.21: G-Linked Protein Receptors

2015-11-22

G-protein Coupled to Ion Channel

G-protein Coupled to Enzyme Adenylyl

Cyclase

G-Protein Linked Receptors and Ca 2+

10

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Ca2+ responsive proteins: Calmodulin (CaM for Ca2+ modulated

protein) & CaM Kinase

CaM (calcium modulated protein, or Calmodulin) regulates serine and threonine

kinases
-i.e., myosin light chain kinase (activates smooth muscle contraction)
-i.e., CaM Kinase II in nerve synapse (alters neurotransmitters secretion)

G-Linked Protein Receptors

11

2015-11-22

G-protein signalling

G-Linked Protein Receptors and cAMP

12

2015-11-22

Ca+ responsive proteins: Calmodulin

G-Linked Protein Receptors

13