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  • 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

  • firstmessenger,” 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 arecoupledto 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

  • subunit dissociates from the rest of the G-

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  • protein.

  • In this particular pathway, the alpha subunit

  • activates phospholipase C, or PLC.

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  • This enzyme acts on the molecule

  • phosphatidylinositol 4,5-bisphosphate, also

  • called PIP2.

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  • PLC cleaves PIP2 into two molecules: inositol

  • 1,4,5 triphosphate (IP3) and diacylglycerol

  • (DAG).

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  • IP3 is a small, water soluble molecule that is

  • released into the cytosol, and travels to the

  • endoplasmic reticulum.

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  • As you have seen in previous lectures, the

  • endoplasmic reticulum stores a large of amount

  • of calcium in the lumen.

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  • IP3 binds to a ligand-gated calcium release

  • channel in the membrane of the endoplasmic

  • reticulum, and calcium flows into the cytosol.

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  • At the same time that IP3 is initiating calcium

  • release, DAG is migrating through the plasma

  • membrane to activate Protein Kinase C (PKC).

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  • The “C” in PKC is named because calcium is

  • necessary for full activity of this kinase.

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  • The calcium released from the ER by IP3

  • assists in full activation of PKC.

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  • Once activated, PKC phosphorylates a number

  • of intracellular targets, thus transmitting the

  • initial message of the hormone binding to the

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  • hormone receptor.

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  • In order to terminate this signal, calcium is

  • resequestered in the endoplasmic reticulum and

  • PIP2 is reformed.

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  • The alpha subunit of the G-protein hydrolyzes its

  • bound GTP into GDP, and the G-protein

  • reassociates.

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  • This restores the resting state of the cell so that

  • another hormone can initiate cellular effects.

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  • Today we have looked at two of the major

  • mechanisms by which G-proteins operate within

  • a cell.

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  • This is one of the major ways in which

  • hydrophilic hormones are able to exert

  • intracellular effects.

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  • Please review this video as many times as

  • needed to familiarize yourself with the G-protein

  • signaling pathways.

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ホルモンはどのようにGタンパク質シグナル伝達経路を使用しています。基本のビデオレビュー。 (How Hormones Use G-protein Signaling Pathways: A Video Review of the Basics.)

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    陳秋汝 に公開 2021 年 01 月 14 日
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