LEC20: Channel Regulation by Second Messengers Flashcards
what is faster: ligand-gated channels response to trasmitters, or signaling pathways involving second messengers?
ligand-gated channels are faster
signaling patways involving second messengers take seconds to minutes
where is Ca2+ sequestered in cells?
storage organelles, particularly sarcoplasmic reticulum and endoplasmic reticulum
what are the different triggering mechanisms to release Ca2+ into the ytoplasm?
1) IP3 receptor (in the ER)
2) Ca2+-responsive receptor, ryanodine receptor (both ER & SR)
what is the relatino of IP3 and ryanodine Ca2+ receptors?
they are proteins that form homologous Ca2+ channels
otherwise, the receptors are unrelated
how is IP3 produced?
how does it trigger Ca2+ release?
1) GPCRs or RTKs stimulate PLC, phospholipase C, which cleaves PIP2 into DAG (remains in lipid bilayer), and IP3, (diffuses into cytoplasm)
2) IP3 reaches the ER membrane, binds to its receptor
3) IP3 binding induces conformational change, opens the ER channel
4) Ca2+ floods out of ER into cytoplasm
what kind of Ca2+ release do ryanodine receptors participate in?
CICR, Ca2+-induced-Ca2+ release
what do the ryanodine receptors provide? what do they work with?
amplification of Ca2+; provide the additional Ca2+ needed to supplement Ca2+ signals from voltage-gated Ca2+ channels, nAChRs, and NMDA-type glutamate receptors
how is the ryanodine receptor mechanism controlled?
by positive feedback:
ryandodine receptor has high affinity binding site, which activates the channel, and low affinity site, which inhibits the channel
initial Ca2+ comes in, opens ryanodine channels, binds high affinity site, increases chance channel will be open
explosive positive feedback
once there’s sufficient [Ca2+], low affinity site is bound, shuts down the channel b/c of **inhibitory binding of Ca2+ **
thus receptor’s inhibited by high Ca2+ concentrations, so when Ca2+ level is sufficiently high, inhibits ryanodine receptor for releasing more
do not get excessive Ca2+ increase
when are Ca2+ stores replenished in ryanodine receptor?
pds of relaxation
what depletes PIP2?
PLC, phospholipase C
when PIP2 is abundant, is PLC activity high/low, and what is speed of is inactivation of K+ channels?
when PIP2 is depleted, how is PLC activity, and how is inactivation of K+ channels affected?
low **PLC **activity = high PIP2 = retarded inactivation of K+ channels
**high PLC **activity = depleted PIP2 = rapid inactivation of K+ channels (b/c there’s no competition for ball-and-chain)
how does PIP2 impact voltage gated K+ channel inactivation?
when does this action get stymied?
PIP2 is on inner leaflet of cell membrane
PIP2 has **negatively charged head group **
PIP2’s head group interacts w/ positively charged residues of proteins near the membrane, such as K+ channel’s “ball and chain,” positively charged region at cytoplasmic N-terminus of each subunit
PIP2 (-) thus attracts N-terminal region of voltage gated K+ channel (+)
this **slows channel inactivation **
HOWEVER, when PLC is active, PIP2 is depleted, channel can inactivate rapidly
what is the structure of a photoreceptor cell?
inner segment: leak K+ channel (hyperpolarizing), Na+/K+ ATPase
outer segment: Na+ and Ca2+ cGMP-gated channel, Na+/Ca2+ Exchanger
which inner segment channel provides predominant membrane conductance? what is the effect?
Leak type K+ channel
allows K+ to leave
is a hyperpolarizing channel
when is the cGMP gated chanel open?
what is this called? explain
what is its effect on the Vm of the cell?
**open **when cGMP levels are high in the cell
this means **in the dark **
this is the dark current: inward current in outer segment, outward current in inner segment; get **net movement of positive charges **from outer segment –> inner segment –> out of cell
-40 mV is the Vm
what is the dark current?
contributions of diff photoreceptor channels to overall membrane conductance, which keep Vm at -40 mV in darkness
current flow:
1) charges enter through Na+/Ca2+ channels
these repel K+ ions from inner segment
2) Na+/K+ ATPase in inner segment maintains the K+ and Na+ gradients
3) Na+/Ca2+ antiporter removes Ca2+ from the cell
what does light do biochemically w/in the photoreceptor?
reduces cellular [cGMP]
decreases current flowing through the cGMP-gated channels in outer segment of the rod
dark current is diminished
membrane hyperpolarizes as Vm moves toward K+ equilibrium potential
this is a graded response
describe pathway of cGMP-mediated decrease in dark current
what happens to membrane when dark current diminishes?
membrane hyperpolarizes as inner current’s contribution to membrane potential is reduced, and Vm moves toward K+ equilibrium potential
what is photoreceptor’s response to a stimulus ?
graded, not all or none like depolairzing action potentials of nerve/muscle
what is the cGMP-gated channel of photoreceptor an example of ?
nucletide-gated ion channels; play role in olfactory (smell) neurons
what is the effect of beta/gamma subunits of G protein on the membrane?
membrane-delimited effect; do not communicate w/ cytoplasmic enzymes
what mediates slowing of the heart when body is at rest?
G-beta/gamma-mediated channel via GPCRs, muscarinic receptors, that couple to Go and Gi
what is the muscorinic receptor?
an Ach receptor, GPCR, that couples to Gi and Go (all beta/gamma, no alpha subunit to Go)
what happens when muscorinic receptor is activated?
G-alpha-I stays in the membrane
but G-beta-gamma subunits are liberated, they can directly interact w/ a Kir, GIRK
they increase its probability of being open
the beta/gamma subunits associated w/ it drive the membrane to be more negative upon repolarization
what is GIRK?
G-protein-regulated inward rectifying K+ channel; channels open rarely, for short durations w/o a drug; adding Ach directly into the GIRK increases probability the channels open, showing effect of the drug was membrane-delimited (b/c did not have response when Ach was just injected into bathing solution - had to be directly into the GIRK)
how does Ach activate GIRK?
very rapidly; through a membrane-delimited mechanism
what controls heart rate?
the Ach-activated GIRK
what dominates the membrane conductance of pacemaker cells between action potentials?
GIRK channel
why shut off inward-rectifying K+ channels during long cardiac action potential?
prevents what would be a large K+ current from repolarizing the membrane prematurely
what happens when action potential ends, cell begins to repolarize?
GIRK channels return to high conductance state; Vm thus becomes more negative; takes long time for cell to spontaneously depolarize to threshold for triggering next action potential
what is Ach’s effect on intervals btwn pacemaker action potentials?
Ach increases interval, b/c activates GIRKs through membrane-delimited G-beta/gamma pathway
