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Hormones are constantly floating through our
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bloodstream.
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At any given point in time you may have growth
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hormone, thyroid hormone, or
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luteinizing hormones coursing through your
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circulation. Some of these hormones, such as
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the steroid hormones, can pass directly into
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cells and bind to intracellular receptors.
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Others, such as protein and peptide hormones
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are hydrophilic, and must bind to receptors in
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the plasma membrane of target cells.
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This brings up an important point: How does the
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extracellular signal of a hormone get transmitted
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into the cell?
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This is commonly accomplished using second
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messengers: small molecules such as cAMP or
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calcium.
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Second messengers relay information from the
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first “messenger,” the hormone, into the cell.
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These second messengers are often produced
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using common proteins associated with the
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plasma membrane called G-proteins.
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G-proteins are “coupled” to receptors in the
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plasma membrane of the cell. G-protein coupled
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receptors can mediate the responses to signals
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such as hormones and neurotransmitters.
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Many different types of ligands can activate G-
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proteins such as fatty acids, proteins, peptides,
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or amino acids.
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Interestingly, about half of all known drugs work
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through G-protein coupled receptors.
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Let’s take a closer look at how G-protein
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signaling mechanisms work. Hormones floating
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through the bloodstream may circulate freely or
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may be complexed with binding proteins.
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In the bloodstream, the hormone dissociates
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from any associated binding proteins and moves
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out of the capillary and into the interstitial fluid.
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The hormone then binds to a hormone receptor
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in the plasma membrane of a target cell.
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The hormone receptor is associated with a G-
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protein, as shown here, which is attached to the
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cytoplasmic side of the plasma membrane.
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The G-protein is responsible for relaying the
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hormonal information to downstream signaling
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pathways within the cell.
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They can be coupled to enzymes or ions
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channels in the plasma membrane.
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Each type of G-protein is specific for one of
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these signaling pathways.
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G-proteins have 3 subunits: an alpha-subunit, a
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beta-subunit, and a gamma-subunit.
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When the G-protein is in an inactive state, the
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alpha-subunit has a bound guanosine-
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diphosphate, or GDP.
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The binding of the hormone to the G-protein
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coupled receptor initiates a conformational
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change in the G-protein.
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This stimulates the alpha subunit of the G-
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protein to exchange its bound GDP for a GTP.
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With this GTP bound,
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the G-protein is in an active state. The activated
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G-protein dissociates into the alpha subunit, and
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a beta-gamma complex.
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The actual target of the activated subunit
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depends on the G-protein that is activated.
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In this video, we will first examine the pathway is
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which cAMP serves as a second messenger.
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The G-protein in this case is a stimulatory
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protein called GS.
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The activated alpha-subunit of GS binds to the
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enzyme adenylyl cyclase.
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This enzyme converts adenosine tri-phosphate
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(ATP) into cAMP.
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cAMP can serve directly as a signaling
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molecule, or it can act indirectly through
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activation of proteins within the cell.
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For example, 4 cAMP molecules can bind to the
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regulatory subunits of Protein Kinase A (PKA).
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This allows the catalytic subunits of PKA to
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dissociate, and PKA can then phosphorylate
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intracellular targets.
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The response of a cell to cAMP and PKA activity
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depends on the cell itself.
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A wide variety of hormones utilize cAMP and G-
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protein signaling such as ACTH, Glucagon, LH,
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PTH and TSH.
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For example, the hormone glucagon can travel
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through the bloodstream to the liver and bind to
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G-protein coupled receptors.
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This initiates an increase in cAMP, which leads
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to the breakdown of glycogen in the liver.
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Since many hormones and neurotransmitters
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rely on the cAMP signaling pathway, the
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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
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very different response than an increase in
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cAMP in a renal cell or in an adipocyte.
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For proper cell function, the cell must also be
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able to stop the G-protein signaling pathway
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after it has accomplished its task.
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To terminate this signal, the cAMP must be
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broken down using the enzyme cAMP
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phosphodiesterase.
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The catalytic subunits of PKA then reassociate
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with the regulatory subunits.
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In order for the G-protein to become inactivated,
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the alpha-subunit must hydrolyze its bound GTP
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back into GDP using its GTPase activity.
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The alpha subunit then reassociates with the
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beta-gamma complex, and the G protein is once
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again back in an inactive state.
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The cell is then ready to be stimulated by
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another hormone.
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G-proteins can also initiate another common
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signaling pathway that utilizes intracellular
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calcium as a second messenger.
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Once again, the hormone dissociates from any
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complexed binding proteins and moves out of
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the capillary and into the interstitial fluid.
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The hormone then binds to a G-protein coupled
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hormone receptor in the plasma membrane of
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the target cell.
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The G-protein in this signaling pathway is called
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Gq.
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The alpha subunit of the G-protein exchanges its
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bound GDP for GTP, and the activated alpha
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subunit dissociates from the rest of the G-
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protein.
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In this particular pathway, the alpha subunit
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activates phospholipase C, or PLC.
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This enzyme acts on the molecule
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phosphatidylinositol 4,5-bisphosphate, also
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called PIP2.
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PLC cleaves PIP2 into two molecules: inositol
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1,4,5 triphosphate (IP3) and diacylglycerol
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(DAG).
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IP3 is a small, water soluble molecule that is
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released into the cytosol, and travels to the
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endoplasmic reticulum.
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As you have seen in previous lectures, the
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endoplasmic reticulum stores a large of amount
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of calcium in the lumen.
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IP3 binds to a ligand-gated calcium release
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channel in the membrane of the endoplasmic
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reticulum, and calcium flows into the cytosol.
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At the same time that IP3 is initiating calcium
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release, DAG is migrating through the plasma
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membrane to activate Protein Kinase C (PKC).
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The “C” in PKC is named because calcium is
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necessary for full activity of this kinase.
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The calcium released from the ER by IP3
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assists in full activation of PKC.
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Once activated, PKC phosphorylates a number
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of intracellular targets, thus transmitting the
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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
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resequestered in the endoplasmic reticulum and
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PIP2 is reformed.
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The alpha subunit of the G-protein hydrolyzes its
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bound GTP into GDP, and the G-protein
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reassociates.
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This restores the resting state of the cell so that
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another hormone can initiate cellular effects.
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Today we have looked at two of the major
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mechanisms by which G-proteins operate within
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a cell.
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This is one of the major ways in which
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hydrophilic hormones are able to exert
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intracellular effects.
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Please review this video as many times as
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needed to familiarize yourself with the G-protein
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signaling pathways.