PIP2 KCNQ Flashcards
What are KCNQ channels?
The Kv7 or KCNQ family of voltage-gated K+ channels regulates neuronal excitability, cardiac pacemaking, and hearing
Why are KCNQ channels significant for PIP2 modulation of channels?
Of all the channels in Fig.1, the KCNQ channels are the ones whose regulation by membrane PIP2 is most obviously tied to physiological functions.
How are KCNQ currents affected by GPCR’s (who)?
Their current (M-current) is suppressed by activation of Gq/11-coupled receptors through the activation of PLC and depletion of PIP2 (Delmas and Brown, 2005)
How do we know that GPCR effects on M currents relate to PIP2?
The suppression by Gq/11-coupled receptors (Horowitz et al., 2005) or by inducible translocation of PIP2 5-phosphatase (Suh et al., 2006) takes only 10 s, which is comparable to the estimated time course for the depletion of membrane PIP2 by these maneuvers
What is the significance of Gq suppression time of M currents?
This observation means that PIP2 takes no more than a few seconds to dissociate from the channel protein.
How does the M current recover?
The recovery of current from inhibition needs the resynthesis of PIP2 from PI by the sequential actions of PI 4-kinase and PIP 5-kinase (Suh and Hille, 2002)
How long does it take for the M current to recover and what does this indicate?
Current recovers in ∼100–200 s, which is consistent with estimates of the slow resynthesis of membrane PIP2
How are KCNQ channels affected by application of PIP2?
Direct application of PIP2 to excised membrane patches increases the channel open probability and slows rundown (Li et al., 2005).
How might KCNQ’s recognize PIP2?
As in other channels, a polybasic domain in the C terminus close to the last transmembrane segment (S6) might be involved in the recognition of membrane PIP2
Mutations where on KCNQ are important for PIP2 sensitivity?
A point mutation in that region (H328C) significantly reduces sensitivity to PIP2 and increases susceptibility to bradykinin receptor-induced inhibition (Zhang et al.,2003)
Several candidate basic residues around that histidine could potentially be binding sites.
What else is bound near the basic resides around the histidine region found by Zhang?
They are near or overlap with two putative calmodulin binding sites, a theme reported for other channels (Kwon et al., 2007) and numerous other PIP2 binding proteins (McLaughlin et al.,2002)
What do binding site overlaps suggest about PIP2 binding on KCNQ?
KCNQ channel coupling to PIP2 might also be regulated by calmodulin binding to the channels (Gamper and Shapiro, 2003).
Is it likely that there are other phosphoinositides that bind to KCNQ?
PIP2 may be the only phosphoinositide for KCNQ channel activation in intact cells.
Why might PIP2 be the only PI for KCNQ channel activation?
Selective depletion of PIP2 using an engineered chemical dimerization system almost completely suppressed the current, whereas the activation of PIP 5-kinase augmented the current (Suh et al.,2006).
What suggests that PIP and PIP3 don’t activate KCNQ currents?
PIP and PIP3 might not be able to activate the current well, as there is still complete inhibition in the rapamycin system when they are elevated by action of PIP2 5-phosphatase and 3-kinase, respectively
