Endocrine 2

Front 1

Transmembrane signalling

Back 1

ligand --> receptor --> transducer --> 2nd messenger --> target -->effect

2nd messanger can be:
- extruded
- sequestered
- degraded

Front 2

Glycogenolysis

Epinephrine

Back 2

- inc activity of phosphorylase: catalyze glycogen --> G1P
-inc activity bc inc in -/+ AMP ration --> conversion of phosporylase from dependent AMP, phosphorylase b to independent from AMP, phosphorylase a (a is active form)

--> reversible covalent modification --> phosphorylation, regulate enzyme activity

Front 3

Glycogen synthase

Back 3

- enzyme that catalyze syn of glycogen
- can be phosphorylated at mult sites with complex result on allosteric regulation of enzyme activity

Front 4

Changes in allosteric regulation of an enzyme

Back 4

are used to study regulation by covalent modifications

- advances in methods that determine protein structure (mass sepc) will likely inc the use of structural measurements and dec the use of functional measurements

Front 5

cyclic AMP

Back 5

- synthesized from ATP by adenylate cyclase

Front 6

G protein

Back 6

- regulates adenylate cyclase by G protein cycle
-binding of GTP to G protein produce effect
- hydrolysis of GTP to GDP terminates effects and the release of GDP

Front 7

Lock G protein into active state or inactive state

Back 7

- hydrolysis resistant analogs of GTP can lock a G protein into its active state.

-Analogs of GDP can lock a G protein into the inactive state

- problem: for drugs lack of specificity

Front 8

GAP

Back 8

GTPase activating protein, some systems req for expression of GTPase activity for adenylate cyclas --> GAP resides iwthing Galpha

Front 9

Gs

Back 9

1. stimulate adenylate cyclase
- promote release of GDP from alpha subunit of Gs, bind with GTP, dissociation of alpha
- hydrolysis of GTP stops syn of cAMP
- hormones that stimulate adenylate cyclase activity also stimulate a GTPase activity
- turnover rate GTP slow 1 per min

Front 10

Gi

Back 10

inhibit adenylate cyclase activity
-promote release of GDP from alpha subunit of Gi , bind GTP , dissociation ofr Beta gamma, Gi alpha -GTP inhbits adenylate cyclase catalytic subunit

Front 11

cAMP- dependent protein kinase

aka protein kinase A, PKA

Back 11

- binding cAMP, regulatory subunits release catalytic subunits --> phosphorylates several susbtrates

Front 12

phosphorylase kinase

Back 12

- calmodulin kinase, regulated by Ca binding to a subunit of the enzymes termed calmodulin

Front 13

Phosphatase

Back 13

catalzye dephosphorylation of proteins --> reversing effects of phosphorylation

Front 14

1. cascade of phosphorylation

2. cAMP frequency

3. Phosphorylation

Back 14

1. allows amplification

2. causes a coordinated inc in a differentiated function of a cell, which freq inc energy consumption and catabolic processes. In the endocrine system this func is freq the secretion of a hormone

3. can alter allosteric regulation (inhbiotry and activating) of an enzyme) but also apparent Km of an enzyme

Front 15

Homologous desensitization

Back 15

receptor phosphorylation and internalization

Front 16

Heterologous desensitization

Back 16

mediated by cAMP
1. inc rate in degradation of cAMP by enzyme phosphodiesterase (PDE)
2. inc rate of extrusion of cAMP from cell by active pumping or facilitated diffusion
3. dec in effective activity of cAMP- dependent protein kinase
- free catalytic subunit of cAMP dependent protein kinase has shorter intracellular half life than subunit associated with the R subunit
4. generation of inhbitors of PKA

Front 17

Bacterial toxins: mono- ADP- ribosyltransferases

Back 17

bacterial toxins catalyze the mono-ADP-ribosylation of the G protein alpha subunits. The rxn transfers the ADP ribose moiety of NAD to the target protein

Front 18

Cholera toxin

Back 18

- vibrio cholerae--> responsible for sudden life thretening voluminous diarrhea of the disease cholear
- act by ADP ribosylating G salpha, dramatically retards the hydrolysis of GTP
- persistent activation of adenylate cyclase

Front 19

Pertussis toxin

Back 19

- toxin produced by bordetella pertussis
- cause of the disease pertussis or whooping cough
- pertussis toxin ADP - ribosylates G i alpha which retards the dissociation of GDP from Gi alpha prevents G i alpha from bindng GTP and blocks hormone inhbition of adenylate cyclase
- hormones that stimulate adenylate cyclase --> more potent, their normal effects are exaggerated

Front 20

Both cholera and pertussis toxins block the GTPase activity of a G protein

Back 20

Recombinant analogs of these toxiins lacking ADP- ribosyltransferase activity are now included as antigens in vaccines to protect against disease

Front 21

Tumors

Back 21

ACtivating mutations in G proteins can cause tumors via the persistent signal to perform the cells' differentiated function which leads to cell division

Front 22

GHRH (growth hormone releasing hormone)

Back 22

acts via cAMP to promote synthesis and release of GH from pituitary cells and promotes proliferation of cultured pituitary cells.

Front 23

Drugs

Back 23

- influence cAMP metabolism
- mimic hormones that stimulate adenylate cyclase
- competative inhbitors of hormones

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Histamine

Back 24

ex. histamine- block histamine stimulation of acid secretion in the stomach

Front 25

Beta blockers

Back 25

ex. beta blockers -- prevent epinephrine from activating adenylate cyclase spares the heart

Front 26

Isoproterenol

Back 26

ex. isoproterenol inc cAMP dec smooth muscle tension in the lung during asthmatic attack

Front 27

Methyl xanthine derivatives (caffeine)

Back 27

inhibitors of cAMP phosphodiesterase (PDE)
- some compounds act as adenosine analogs at adenosine receptors which inhbit adenylate cyclase rather than by inhbiting PDE