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BIO315H5 Midterm: Test 1 Review - Lecture 4

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Hai- Ying Mary Cheng
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Test 1 Review Lecture 4
Calmodulin: mediator (regulator) of Ca2+
Calcium-modulated protein
Ca2+ binding protein; no enzymatic activity
Undergoes a conformational change when bound allosterically to calcium
Activates Ca2+/calmodulin-dependent protein kinases
Meadiates processes such as:
-smooth muscle contraction
CaM-kinase II: Calcium calmodulin dependent protein kinase
Made up of 12 subunits
Ser/thr kinase phosphorylates on the residues
Decoding calcium signal
Kinase domain has catalytic activity
Regulatory segment at active site of kinase blocks kinase activity & regulated by calmodulin
Each subunit has phosphorylation site ser/thr residue phosphorylated by CAMK- makes the
kinase activity calcium independent
When phosphorylated, makes Ca2+ activity independent
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Stepwise activation of CaMKII
Each has 2 major domains: amino-terminal kinase (green) and carboxyl-terminal hub (blue)
Linked by regulatory segment
6 CaMKII proteins are assembled surrounded by kinase domains
Complete enzyme has 2 stacked rings
When the enzyme is inactive, the ring exists in a dynamic equilibrium between two states
Compact state kinase domains interact with hub, regulatory segment is buried in kinase active
site and thereby blocks catalytic activity
Inactive state kinase domain has popped out and is linked to central hub by its regulatory
segment, which continues to inhibit the kinase but is now accessible to Ca2+/calmodulin. If
present, Ca2+/calmodulin will bind the regulatory segment and prevent it from inhibiting the
kinase, thereby locking the kinase in an active state
If the adjacent kinase subunit also pops out from the hub, it will also be activated by
Ca2+/modulin, and the two kinases will then phosphorylate each other on their regulatory
segments. This transautophosphorylation further activates the enzyme. It also prolongs the
activity of the enzyme in two ways
1. Traps bound Ca2+/calmodulin so that it does not dissociate from the enzyme until a cytosolic
Ca2+ levels return to basal values for at least 10 seconds
2. It converts the enzyme to a Ca2+ independent form, so that the kinase remains active even
after the Ca2+/calmodulin dissociates from it
This activity continues until the action of a protein phosphatase overrides the
autophosphorylation activity of CaMKII
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CAMKII as frequency decoder of Ca2+ oscillations
A) at low frequencies of Ca2+ spikes, the enzyme becomes inactive after each spike, as the
autophosphorylation induced by Ca2+/aloduli idig does ot aitai the ezye’s
activity long enough for the enzyme to remain active until the net Ca2+ spike arrives
B) At high spike frequencies, the enzyme fails to inactivate completely between Ca2+ spikes, so
its activity ratchets up with each spike. If spike frequency is high enough, the progressive
increase in enzyme activity will continue until the enzyme is autophosphorylated on all subunits
and is therefore maximally activated
G-proteins and ion channels
G-proteins can DIRECTLY activate or inactivate ion channels to change ion permeability
G-proteins can INDIRECTLY regulate ion channels by stimulating phosphorylation OR
regulating production of cyclic nucleotides that are essential for channel function
-can then bind to channels that are regulated by them
Cyclic nucleotides and our sensory world
Smell depends on activation of GPCRs (olfactory receptors) that couple to olfactory-specific G
proteins (Golf)
Golf increases [cAMP], which in turn opens cAMP-gated Na+ channels, causing membrane
In vertebrates, vision is controlled by ion channels that are gated by cyclic GMP
cGMP is continuously synthesized by guanylyl cyclase
changes in [cGMP] are mediated by cGMP phosphodiesterases
Photoreceptor cells respond to decreases in [cGMP]
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