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Endocrine signaling

Molecule secrete by the signaling cell is transported to the target cell via the BLOOD-STREAM

e.g. epinephrine-acts on heart muscle to increase heart rate


Paracrine signaling

Molecule diffuses to neighboring target cells of a different cell type

e.g. testosterone (made in testis) induces spermatogenesis by acting on Sertoli cells and germ cells in neighboring seminiferous tubules


Autocrine signaling

Secreting cells themselves express cell surface receptors for the signaling molecule..."autocrine loops"

e.g. chemokines (small signaling proteins such as interleukins)


Juxtacrine signaling

Molecule stays attached to the signaling cell and binds to a receptor on an adjacent target cell, establishing physical contact between the two cells


Classification of signaling molecules

Lipophilic or hydrophilic


Lipophilic signaling molecules

-Steroid hormones: progesterone, estradiol, cortisol, testosterone, aldosterone, Vit D
-Thyroid hormone: thyroxine
-Retinoids (deriviatives of Vit A): retinol, retinoic acid


Lipophilic signaling molecules receptor location and type

-Found in the cytoplasm and nucleus
-Family of DNA-binding transcription factors (TFs)


Hydrophilic signaling molecules

-AA derived: histamine, serotonin, melatonin, dopamine, norepinephrine, epinephrine
-From lipid metabolism: acetylcholine
-Polypeptides: insulin, glucagon, cytokines, thyroid-stimulating hormone


Hydrophilic signaling molecules receptor location and type

-Includes transmembrane proteins such as G protein-coupled receptors and receptor tyrosine kinases


Cytoplasmic receptors

For lipophilic signaling molecules

(in cytoplasma) in inactive complex w/ HSPs (heat shock proteins i.e. HSP 90). Signal molecule binds, receptor dissociates from HSP-->nucleus-->binds to HRE (hormone response element) in promoter region-->alters rate of mRNA transcription

Receptor + HSP --activated--> nucleus-->HRE-->change transcription


Lipophilic and hydrophobic medications

Lipophilic sign. molecules: oral contraceptives (ethinyl estradiol-derivative of estradiol) has long half-live, hence taken daily

Hydrophilic sign. molecules: taken in moment when needed. e.g. epinephrine for allergic rxns


Effects of glucagon, epinephrine, cortisol, and insulin on glucose metabolism

Glucose deficiency-->pancrease releases glucagon-->↑ blood glucose levels via breakdown of glycogen in liver & inhibits glycogen synthesis

Epinephrine-->stim breakdown of glycogen via glucagon secretion

(If low glycogen stores, then..)cortisol-->stim gluconeogenesis (makes glucose)

Insulin lowers blood glucose via synthesis of glycogen (stores glucose)-->stimulating glycolysis and inhibit gluconeogenesis


What do GEFs do?

(Guanine nucleotide exchange factors (GEFs):

They activate G proteins by turning GDP-->GTP


What do GAPs do?

GTPase-activating proteins

Inactivate G proteins by turning GTP-->GDP


GPCR signaling (Gsα)

G protein-coupled receptor signaling

Gsα (α subunit, s version): mnemonic: "gas". Activation of Gsα stimulates AC (adenylate cyclase)-->turns ATP to cAMP--> cAMP stimulates PKA--> phosphorylates other proteins to alter activity


GPCR signaling (Gtα)

G protein-coupled receptor signaling

*instead of a signal molecule activating GPCR, it is LIGHT that activates it

Activation of Gtα activates cGMP phosphodiesterase (cGMP PDE)-->hydrolyzes cGMP to 5'-GMP

Reduced levels of cGMP cause hyperpolarization of visual cells which is important for vision.


GPCR signaling via Gq, PLC and PKC

Signal molecule binds to GPCR which activates Gq-->stimulates PLC to cleave PIP2 into--->IP3 and DAG

IP3-->causes release of Ca 2+ from ER/SR into cytosol. This ↑ of Ca 2+ causes PKC to move to plasma membrane where it is activated by DAG

Ca 2+ also binds to the protein calmodulin -->activation of Ca 2+ calmodulin-dependent proteins (e.g. CaM kinase, MLC kinase)--> (1)CaM kinase phosphorylates target proteins to alter their activities OR (2) activated MLC kinase phosphorylates myosin light chains --> causes smooth muscle contraction


Diversity of GPRC signaling

Epinephrine can do 2 different things, depending on the cells it is acting upon

1. Binding of epinephrine to β-adrenergic receptors causes relaxation of bronchial (asthma attack) and intestinal smooth muscle (Gsα)

2. Binding of epinephrine to β-adrenergic receptors on heart causes heart contractions (restore rhythms after shock or cardiac arrest)

Why? B/c downstream signaling pathways diverge


β-Agonists and their effects

β-agonist albuterol is a hydrophilic molecule which activates B2-adrenergic receptors.

Given via inhaler/nebulizer to open lungs from asthma, bronchitis, COPD

If unresponsive, can also be given epinephrine b/c it also relaxes bronchial smooth muscle but it also stimulates heart contraction.

Side effect of these β-agonists is tachycardia (rapid heart rate)


Nitric oxide and smooth muscle relaxation

NO (nitric oxide) relaxes smooth muscle.

Made via promoting Ca 2+ calmodulin (in GPCR pathway)

NO stimulates cGMP & so w/ Viagra you get too much cGMP (b/c phosphodiesterase is inhibited)

NO+Viagra=extreme vasodilation and sometimes fatal drop in blood pressure


Antihistamines inhibit G protein-coupled receptor signaling

Allergies caused by histamine (hydrophilic signaling molecule)

Histamine binds to four histamine GPCRs (H1-H4)

Antihistamines are lipophilic, work by blocking histamines binding to H1 GPCR (Zyrtec, Claritin, Benadryl)

Other antihistamines that block H1 receptors can be used as antiemetics and be used to combat motion sickness


Receptor Tyrosine Kinase signaling steps

Kinase: enzyme that helps transfer phosphate groups

1. Signaling molecule binds and this makes the 2 separate pieces come together and form the dimer

2. It autophosphorylates itself

3. These phosphotyrosine residues are recognized by other proteins and they come and bind, then go do their job (activate downstream signaling pathways- either independent or dependent of the monomeric G protein RAS)


RAS dependent

1. Insulin binds to its RTK (receptor tyrosine kinase) (a preformed dimer) causing autophosphorylation

2. Phosphotyrosine residues are recognized and bound by the IRS-1 substrate (insulin receptor substrate 1)

3. IRS-1 is phosphorylated on its tyrosine residues by the insulin receptor

4. Phosphorylated IRS-1 is recognized and bound by GRB-2--> act.RAS and MAPK cascade--> phosphorylation of nuclear proteins-->inc. transcription of glucokinase-enzyme that phosphorylates glucose in the first step of both glycolysis and glycogen synthesis

5. IRS-2 is similar to IRS-1 but has different specificity for adaptor proteins


RAS independent

1. Insulin binds to its RTK (receptor tyrosine kinase) (a preformed dimer) causing autophosphorylation of tyrosine residues.

2. Phosphotyrosine residues are recognized and bound by the IRS-1 substrate (insulin receptor substrate 1)

3. IRS-1 is phosphorylated on its tyrosine residues by the insulin receptor

4. Phosphorylated IRS-1 recruits PI 3-kinase which phosphorylates a phospholipid to make PIP3 (and another phosphoinositides)

5. These act as second messengers that stimulate recruitment of protein kinase B (PKB) to membrane and its activation via phosphorylation

6. Active PKB is known as Akt, phosphorylates many intracellular proteins which affect glucose uptake and storage

(PKB plays role in moving GLUT4 from cytoplasm to plasma membrane

PKB also promotes glycogen synthesis by phosphorylating and inhibiting GSK-3)

Insulin binds to RTK-->autophosphorylation--> recognized by IRS-1 substrate-->IRS-1 phosphorylated by insulin receptor--> Recruits PI 3-kinase--PI 3-kinase makes PIP3 via phosphorylation-->Stimulate recruitment of PKB to membrane and its activation via phosphorylation-->active PKB phosphorylates intracellular proteins-->effects glucose uptake/storage


RAS and cancer

Activating point mutations in RAS (monomeric G protein) lead to many cancers. These mutations decrease intrinsic GTPase activity of RAS and lock it for a longer period in the active or GTP-bound state

Neurofibromatosis: growth of tumors from nerve tissue. Caused by turning off NF-1 gene which makes GAP (which turns RAS off GTP-->GDP)

Absence of NF-1 allows RAS to uncontrollably activate pathways that promote nerve tissue growth


Recognition domains

Adaptor proteins such as GRB-2 and IRS-1 have special domains known as SH2 domains or PTB domains that recognize and bind to motifs on the receptor that contain phosphorylated tyrosine residues


Insulin Resistance

Loss of insulin stimulation of glucose uptake by GLUT4 transporters in adipose and skeletal tissue. There is reduced activation of PKB by insulin in these patients. The site of impairment is probably IRS-1 or IRS-2. Serine/threonine phosphorylation appears to inactivate the IRSs and lead to their degradation



ADP-ribosylation of α subunit of Gs leading to constant activation of AC-->lots of cAMP (Gα in GTP form indefinitely)

Effector: pump H2O and Cl- out (diarrhea)


Liver disease

(Alcoholic liver cirrhosis) the RBC gets loaded w/ cholesterol. High cholesterol also leads to reduced repair of lipids after peroxidation


Gsα examples

Histamine, Epinephrine