Hormones are constantly floating through our

bloodstream.

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At any given point in time you may have growth

hormone, thyroid hormone, or

luteinizing hormones coursing through your

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circulation. Some of these hormones, such as

the steroid hormones, can pass directly into

cells and bind to intracellular receptors.

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Others, such as protein and peptide hormones

are hydrophilic, and must bind to receptors in

the plasma membrane of target cells.

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This brings up an important point: How does the

extracellular signal of a hormone get transmitted

into the cell?

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This is commonly accomplished using second

messengers: small molecules such as cAMP or

calcium.

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Second messengers relay information from the

first “messenger,” the hormone, into the cell.

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These second messengers are often produced

using common proteins associated with the

plasma membrane called G-proteins.

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G-proteins are “coupled” to receptors in the

plasma membrane of the cell. G-protein coupled

receptors can mediate the responses to signals

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such as hormones and neurotransmitters.

Many different types of ligands can activate G-

proteins such as fatty acids, proteins, peptides,

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or amino acids.

Interestingly, about half of all known drugs work

through G-protein coupled receptors.

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Let’s take a closer look at how G-protein

signaling mechanisms work. Hormones floating

through the bloodstream may circulate freely or

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may be complexed with binding proteins.

In the bloodstream, the hormone dissociates

from any associated binding proteins and moves

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out of the capillary and into the interstitial fluid.

The hormone then binds to a hormone receptor

in the plasma membrane of a target cell.

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The hormone receptor is associated with a G-

protein, as shown here, which is attached to the

cytoplasmic side of the plasma membrane.

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The G-protein is responsible for relaying the

hormonal information to downstream signaling

pathways within the cell.

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They can be coupled to enzymes or ions

channels in the plasma membrane.

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Each type of G-protein is specific for one of

these signaling pathways.

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G-proteins have 3 subunits: an alpha-subunit, a

beta-subunit, and a gamma-subunit.

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When the G-protein is in an inactive state, the

alpha-subunit has a bound guanosine-

diphosphate, or GDP.

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The binding of the hormone to the G-protein

coupled receptor initiates a conformational

change in the G-protein.

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This stimulates the alpha subunit of the G-

protein to exchange its bound GDP for a GTP.

With this GTP bound,

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the G-protein is in an active state. The activated

G-protein dissociates into the alpha subunit, and

a beta-gamma complex.

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The actual target of the activated subunit

depends on the G-protein that is activated.

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In this video, we will first examine the pathway is

which cAMP serves as a second messenger.

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The G-protein in this case is a stimulatory

protein called GS.

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The activated alpha-subunit of GS binds to the

enzyme adenylyl cyclase.

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This enzyme converts adenosine tri-phosphate

(ATP) into cAMP.

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cAMP can serve directly as a signaling

molecule, or it can act indirectly through

activation of proteins within the cell.

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For example, 4 cAMP molecules can bind to the

regulatory subunits of Protein Kinase A (PKA).

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This allows the catalytic subunits of PKA to

dissociate, and PKA can then phosphorylate

intracellular targets.

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The response of a cell to cAMP and PKA activity

depends on the cell itself.

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A wide variety of hormones utilize cAMP and G-

protein signaling such as ACTH, Glucagon, LH,

PTH and TSH.

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For example, the hormone glucagon can travel

through the bloodstream to the liver and bind to

G-protein coupled receptors.

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This initiates an increase in cAMP, which leads

to the breakdown of glycogen in the liver.

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Since many hormones and neurotransmitters

rely on the cAMP signaling pathway, the

response of a

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cell will depend on the cell type itself.

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An increase of cAMP in a liver cell will cause a

very different response than an increase in

cAMP in a renal cell or in an adipocyte.

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For proper cell function, the cell must also be

able to stop the G-protein signaling pathway

after it has accomplished its task.

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To terminate this signal, the cAMP must be

broken down using the enzyme cAMP

phosphodiesterase.

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The catalytic subunits of PKA then reassociate

with the regulatory subunits.

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In order for the G-protein to become inactivated,

the alpha-subunit must hydrolyze its bound GTP

back into GDP using its GTPase activity.

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The alpha subunit then reassociates with the

beta-gamma complex, and the G protein is once

again back in an inactive state.

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The cell is then ready to be stimulated by

another hormone.

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G-proteins can also initiate another common

signaling pathway that utilizes intracellular

calcium as a second messenger.

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Once again, the hormone dissociates from any

complexed binding proteins and moves out of

the capillary and into the interstitial fluid.

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The hormone then binds to a G-protein coupled

hormone receptor in the plasma membrane of

the target cell.

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The G-protein in this signaling pathway is called

Gq.

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The alpha subunit of the G-protein exchanges its

bound GDP for GTP, and the activated alpha