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Receptor Mech > PIP2 Revision > Flashcards

PIP2 Revision Flashcards

1
Q

Phosphoinositides are

A

acidic phospholipids of the cytoplasmic leaflet of the membrane with myo-inositol head group

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2
Q

Parent compound of phosphoinositides

A

phosphatidylinositol - 3,4-5 - rise to 7 low abundance POLY phosphoinositides

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3
Q

Phosphoinositides 3 functionsq

A
  1. Mark identity of specific subcellular membrane components
  2. Membrane recognition sites for cytoplasmic proteins
  3. Membrane-delimited second messengers
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4
Q

PIP2 is

A

minority inner leaflet - regulates many ion channel + transporters whose activity is turned off by pathways that deplete PIP2

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5
Q

Who listed 2 functional advatnages

A

Suh and Hille 2008

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6
Q

First funcitonal advantage

A

Higgleman 1996

Silencing during transportatin and recycling

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7
Q

Second advantage

A

NT - increase PLC - regulated by incoming signals

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8
Q

PIP2 regulates which ion channels

A
  1. VGCC - N and P/Q
  2. TRP
  3. Two-P K
  4. Kir
  5. Transporters: NXC + PMCA
  6. Ca2+ release channels IP3 R + RYR
  7. Renal epithelial Na+ channels ENAC
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9
Q

Kir mutation

A

Plaster 2001 - exacerbated by enhanced sensitivity to PIP2 depletion by modulating stimuli

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10
Q

PIP2 does what to Kir’s

A

Stabilize Po

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11
Q

What residues in Kir’s are important for PIP2 binding?

A
  1. C-terminal fusion proteins - Huang 1998 bind directly (1.1, 2.1, 3.1,3.2)
  2. Homologous arginine in M2 of Kir 1.1, 2.1, 5.1,6.2 Huang 1998
  3. Lopes 2002 basic + hydrophobic residues in NTD and distal CTD
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12
Q

Implications of residues in PIP2 binding to Kir

A

Affinity + specificity to Kir2.1

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13
Q

Kir - apparent PIP2 affinity regulated by other signals - what are these?

A
  1. PKA - Kir 1.1 - Liou 1999 antibodies
  2. Kir 3.1-3.4 BY+ intracellular Na+ Huang, 1998
  3. Intracellular ATP Kir6.X - decrease PO Baukauwitz, 1998
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14
Q

Initial leads came from

A
  1. KirBac1.1 - inhibiited by PIP2 + 3 -> Kuo 2003 crystal structure
  2. CTD Kir 3.1/2.1 Nishida + MacKinnon 2002
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15
Q

First homology model

A

Logotethis 2007 - binding site is clustered in the same region in channel space as by and Na+ - regulates open.close and coordinates action of gating modifiers

Kir6.1

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16
Q

Analogous homology model

A

Haider - dock inositol phosphates surrogates for phosphoinositide head

Kir6.2

17
Q

Final chimera

A

Membrane KirBac1.1. CTD Kir3.1

Ring-like cloud of basic residues near putative bilayer - likely binds

18
Q

Homology model binding Kir6.2

A

4 binding sties each at interface between homotetrameric subunits - binds by contact with 6 basic residues and some H bonding

Maximal distance from bilayer - strain assists opening

19
Q

Of all the ion channels regulated by PIP2,

A

PIP2 regulation of Kv7 most tied to physiological function

20
Q

What type of GPCR inhbiits Kv7?

A

Delmas and Brown

Gq/11 suppresses M current by activation of PLC which depletes PIP2

21
Q

What studies showed that time course of Kv7 inhibition coincides with PIP2 depletion?

A
  1. Horowitz 2005 - Gq/11 suppression
  2. Suh 2006 - inducible translocation of PIP2-5 phosphatase
    10s
    comparable to time taken for PIP2 depletion by these maneuvers
22
Q

What showed that recovery of M-current was related to PIP2 resynthesis?

A

Suh and Hille, 2002 - 100-200 ms - requires PI4K and PI5K sequential action

23
Q

What does direct application of PIP2 do?

A

Li 2005

increases pO and slows rundown

24
Q

Why might PIP2 be the only phosphoinositide that acts on Kv7 in in tact cells?

A
  1. PIP2 - deplete engineered chemical dimerization system - suppress M - whereas augmented by PIP5 kinase Suh 2006
  2. PIP + PIP3 still complete inhibition in rapamycin system when these are activated by PIP2 - 5 phosphatase and 3 kinase
  3. PI 3,4 P2 - little affect on M current in excised patches
25
Q

What do we know about the binding site for PIP2 on Kv7?

A
  1. polybasic residues in C terminus close to S6
  2. H328C point moutation - increase susceptibility to BKR mediated inhibition Zhang 2003
  3. candidate basic residues around this histidine
26
Q

Overlap of binding site of PIP2 on Kv7?

A
  1. Kwon 2007 - 2 putative calmodulin binding sites- theme reported for other channels
  2. McLaughlin - many PIP2 binding proteins
  3. Gamper and Shapiro - 2003 -> calmodulin binding might modulate PIP2 binding
27
Q

How is PIP3 made?

A

3’ phosphorylation by PI3K

28
Q

What does PIP3 do?

A

PH and PH-like proteins to membrane surface (Englemann, 2006)

29
Q

How does PH recruitment to membrane surface lead to Akt phosphorylation?

A

Proximity ->

  1. PI binding proteins - PDK-1 Alessi 1997
  2. Complexes such as mTorc2 - Sabrassov 2004/5
    - > phosphorylate Akt
30
Q

Effects of Akt

A
  1. Mostly inhibits
  2. Cell growth
  3. Cell cycle
  4. Cell survival
31
Q

Example of Akt signalling

A

FKHR-L1

14-3-3 Brunet,2001

Retention in cytosol = no transcription of FKHR-L1 regulated genes

32
Q

Intracellular calcium signals affect PIP2 how

A
  1. Depletion by Ga from Gq-GPCRi, Gby from GiS or Rac for PLCb2
  2. Accelerates PI kinases that lead to resynthesis Loewe 2007
33
Q

Example of pathway that accelerates kinases

A

NCS-1 - wide sprectrum of actions - Burgogne + Weiss, 2001

Up regulation of PI4K - facilitate first step of PIP2 resynthesis Zhao,2001

34
Q

PLC activated by

A

Ga - from Gq-GPCR

35
Q

PLC does what?

A

binds PIP2 + translocates to surface membrane

at surface phase - 1000x fold greater concentration of PIP2 than in cytosol

depends on Ca2+ i activation

IP3 + DAG

36
Q

DAG does what?

A

binds to C1 domain of PKC

37
Q

PKC is

A

1/10 S/K - classified into 3 families based on ligand cofactor requirements - mediates Ca2+ downstream signalling

38
Q

Consequences of PLC activation

A
  1. PIP2 depletion
  2. Calcium release
  3. PKC activation
  4. Channel inhibition
39
Q

How do IP3R and RYR mediate differential responses?

A
  1. IP3 high freq. Ca2+ oscillations

2. RYR low freq - PKC -> CaMKII -> RYR

Receptor Mech (25 decks)

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