Download Biochemistry Objectives 38 and 39

Biochemistry Objectives 38 and 39
1.
Hormones:
a.
Biochemical properties: synthesized in endocrine glands, effective at low
concentrations in blood due to signal amplification, have short half-lives,
exert multipoint control on numerous targets, and are feedback regulated
by themselves, their products, and the CNS
b.
Chemical classes: amines, peptides, and steroids; they are classified also
by their binding receptor properties:
a. I: intracellular receptor
b. IIA stimulatory: increased cAMP
c. IIA inhibitory: decreased cAMP
d. IIB: IP3, Ca2+, DAG
e. IIC: receptor tyrosine kinase
f. IIC’: soluble tyrosine kinase (JAK)
g. IID: increased cGMP
2.
G-proteins:
a.
General mechanism of signal transduction: GDP dissociates from the 
subunit and is replaced by GTP causing a subsequent  subunit
dissociation from 2  and 2  subunits. The  subunit then activates an
effector until GTP is hydrolyzed to GDP and the process starts over.
b.
Second messengers influenced by:
a. Gs: adenylyl cyclase activation
b. Gi: adenylyl cyclase inhibition
c. Gq: PLC activation
d. Gt: cGMP phosphodiesterase activation
c.
cAMP activation of PKA: 4 cAMP bind to 2 regulatory subunits to
dissociate the regulatory subunits from the catalytic subunits. The
catalytic subunits are active until 5’-AMP phosphodiesterase turns cAMP
into AMP and the regulatory subunits reassociate with the catalytic
subunits.
d.
Signaling through IP3, Ca2+, and DAG: PLC cleaves PIP2 into IP3 and
DAG. 3 IP3 molecules bind to the smooth ER, allowing Ca2+ into the
intracellular space.
e.
Ca2+ and CaM-dependent kinase: 4 Ca2+ bind calmodulin which in turn
activates CaM-dependent kinase to initiate cellular responses including
increased insulin synthesis, fuel storage, and cell growth/proliferation.
f.
Ca2+ and DAG activation of PKC: PKC has 2 C1 subunits (binds DAG)
and 1 C2 subunit (binds Ca2+). When Ca2+ and DAG increase, PKC binds
to them and activates to initiate cellular responses including increased
insulin synthesis, fuel storage, and cell growth/proliferation.
3.
Overproduction of cAMP:
a.
Cholera toxin: ADP-ribosylation of the s subunit inhibiting ATP
hydrolysis and constitutively activating s and thus, adenylyl cyclase
(cAMP overproduction).
b.
Pertussis toxin: ADP-ribosylation of the i subunit inhibiting interaction
with the receptor and thus, rendering the i subunit inactive and adenylyl
cyclase uninhibited (cAMP overproduction).
4.
Visual cycle:
a.
Vitamin A:
a. Retinol: transported by RBP and binds to CRBP, acting as a nuclear
hormone to induce spermatogenesis in males and prevention of fetal
resorption in females.
b. Retinoic acid: two isomers: all-trans retinoic acid binds RAR while 9cis retinoic acid binds RXR. Bound RAR and RXR form a
heterodimer that helps control gene expression important for
embryonic differentiation, cell growth, and differentiation.
c. Retinal: required for vision; see below
b.
Functions of:
a. Retinal isomerase: turns all-trans retinal into 11-cis-retinal
b. 11-cis-retinal: binds to opsin protein to form rhodopsin
c. Opsin: Gt-protein coupled receptor that binds to 11-cis-retinal to form
rhodopsin
d. Rhodopsin: active photoreceptor that is activated by a photon of light
(when activated, 11-cis-retinal turns back to all-trans retinal)
e. Metarhodopsin II: downstream, active Gt-protein coupled receptor
where Gt dissociates to activate visual stimulation
f. Transducin: Gt molecule that signals metarhodopsin II activation
g. Phosphodiesterase: effector of transducin; catalyzed conversion of
cGMP to GMP
h. cGMP: high cGMP induces Na+/Ca2+ influx
i. Low intracellular Na+: low intracellular Na+ signals a hyperpolarized
state, and slows the release of glutamate and dark sensation; low
intracellular Na+ signals light sensation
j. Rhodopsin kinase: phosphorylates rhodopsin to lower its activation
k. Arrestin: binds to phosphorylated rhodopsin to completely terminate
rhodopsin activity
c.
Low intracellular Ca2+ and recoverin restoring cGMP: low Ca2+ inhibits
cGMP phosphodiesterase and stimulates recoverin which stimulates
guanylyl cyclase to make cGMP
5.
Vitamin A deficiency:
a.
Embyonic development: retinoic acid is important in embryonic
differentiation, and deficiency can lead to CNS, craniofacial, and cardiac
malformations
b.
Defective night vision: since retinal is important in visual processing,
retinal deficiency leads to defective night vision because light signals can
not be processed
c.
Respiratory and GI infections: retinol and retinoic acid are important for
regulating keratin synthesis. When there is a deficiency, excessive
keratinization occurs, causing drying and loss of mucosal lining in the
respiratory/GI tracts, and increased susceptibility to pathogen invasion.
d.
Eye damage: retinol and retinoic acid depletion causes keratinization of
the eye which causes conjunctival drying, Bitot’s spots, and corneal
drying. This can ultimately cause a perforation of the cornea and
increased susceptibility to pathogenic invasion.
6.
Vitamin A toxicity causes and consequences: excess Vitamin A causing an
increase in retinol over RBP binding capacity can be toxic due to increased levels
of toxic unbound retinol. Retinoic acid increases are extremely dangerous due to
their toxicity and lack of feedback inhibition. Vitamin A toxicity presents as
dermatitis, hepatosplenomegaly, and teratogenic effects in pregnancy.