Block3 1.g-Proteins

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3 Signaling Schemes:
Endocrine, Paracrine, Autocrine

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Endocrine - hormones travel in the blood stream after being secreted by a distant gland
Paracrine - Between two cells that are adjacent or neighboring eachother
Autocrine - Cell stimulating itself

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GPCR (G-protein coupled receptors)

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7 transmembrane domains (H1-7)
4 exterior regions E1-4 (NH3+ exterior)
4 interior regions C1-4 with C3 and C4 (COO-) interacting with trimeric G-proteins

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Trimeric g-protein activation

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GPCR activation causes association of the COO- region with a membrane associated trimeric g-protein bound with GDP. The association causes release of GDP for GTP activating it and causing the alpha subunit to dissociate from the Beta/gamma. The alpha associates with an effector protein, that transduces signals into the cell (could cause hormone release)

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Adenylyl cyclase - the most common Effector protein of GPCR's

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Catalyze formation of cAMP -> Protein Kinase A...

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Opposing GPCR signaling: Adenylyl cyclase

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GPCR signals may have one version that is stimulatory (Epinephrine, glucagon, ACTH) but another that is inhibitory (PGE1, Adenosine) on the same effector molecule (Adenylyl cyclase)

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Second Messengers:
cAMP, cGMP, DAG, IP3

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cAMP -> PKA
cGMP -> PKG and opens cation channels in rods
DAG -> PKC
IP3 -> Opens calcium channels in the ER

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cAMP, PKA and Transcription

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Cyclic AMP binds up regulatory subunits on PKA, allowing PKA to phosphorylate CREB. It also activates MAPK, which activates CREB binding protein (P300). This binds over phospho-CREB that is already bound on DNA (CRE)

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Different tissues are stimulated to increase cAMP by different hormones, and the effects is has are different in different tissues.

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Epinephrine = Beta-adrenergic receptor

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CLINICAL: Bacterial GPCR Activation / Inactivation.
1. Cholera
2. Whooping cough

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1. Cholera. Caused by Vibrio cholerae. Toxin causes G-alpha stimulatory subunit to remain active, causing high cAMP -> PKA -> CFTR activity -> large chloride and water loss from intestinal epithelial cells, resulting in diarrhea.
2. Whooping cough. Bordatella purtusis. Toxin inhibits the G-alpha inhibitory subunit, resulting in same thing. Here the overstimulation causes excessive mucous secretion in the lung epithelia

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CLINICAL: Heart failure.

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Normal muscle contraction mediated by adrenalin stimulation of GPCR, Calcium release from the sarcoplasmic reticulum into the cytosol, then it should suck it all back up. Various ways you could get elevated calcium levels. The change from low to high calcium levels is what makes the contraction functional. If not re-sequestering the calcium back into the sarcoplasmic reticulum, treatment can be with Beta blockers, but you must test the doses carefully. In a nutshell: Abnormal signaling is causing calcium to stay elevated in the cytoplasm, and not getting properly sequestered back into the sarcoplasm. You want a good shift in calcium levels between sarcoplasm and cytoplasm.

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Phospholipase C, DAG/IP3/Ca2+ and PKC

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Phospholipase C is an effector molecule of a GPCR. Upon activation, it cleaves PIP2 into IP3 and DAG. IP3 Causes calcium release from ER, this activates PKC. PKC can bind DAG which seems to anchor it into plasma membrane. It then is free to phosphorylate different items

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PIP2

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PI 4,5 Bisphosphate

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Smooth Muscle Relaxation

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Starts with:
Acetylcholine GRCR (on the epithelial cells of blood vessel) ->
Phospholipase C -> IP3
Calcium/Calmodulin ->
NO synthase -> Nitric oxide
NO Receptor (on neighboring smooth muscle cells) cells-> PKG -> Relaxation of muscle cells