Sodium Revision

Question 1

First evidence that TTX was a NaV specific blocker

Answer 1

Sucrose Gap - Voltage clamp of lobster giant axons
94nM

no effect on K+ current

Narahashi, Moore and Scott, 1964

Question 2

Structural determination

Answer 2

Tsuda 1964

Guanine

+ one positive charge at physiological pH

Question 3

External block

Answer 3

TTX block outside nerve membrane

Blocking action devoid on internal perfusion

Narahashi, Anderson and Moore, 1967

Question 4

Support of cationic block

Answer 4

Hille, 1975

Permeability titrates away at increasingly low pH owing to the presence of protons

Question 5

TTX block in relation to gating

Answer 5

Keynes and Rojas, 1974

Measured gating currents of Nav not affected by TTX

Plugging blocks flow from outside even though gating mechanism normally operates upon depolarizing stimulation

Question 6

One-to-one stochiometric block suggests

Answer 6

Q, Y + N, 1985

Characteristic of single ion channel not affected

Observation open decreases dose-dependently

Question 7

Relative sizes of subunits

Answer 7

250

33-37

kDA

Question 8

Hairpin P loop

Answer 8

S5-S6 of DIII

Question 9

TTX binding sites

Answer 9

All S5-S6 of domains

Question 10

u-Connotoxin binding site

Answer 10

Only S5-S6 of DII

Question 11

NT binding site 2

Answer 11

S6 of DI and DiV

Question 12

NT binding site 3

Answer 12

S3-S4 linker DIV

Question 13

NT binding site 4

Answer 13

S1-2 linker DII

Question 14

NT binding site 5

Answer 14

S6 DI and S5 DIV

Question 15

Beta subunit important for

Answer 15

Voltage dependency 
gating
cell adhesion
signal transduction
expression at PM

Question 16

IFMT is where

Answer 16

Between DIII and DIV

Question 17

S4 time course associates with

Answer 17

onset of inactivation or slow ON gating charge

Question 18

Why is S4 not inactivating particle?

Answer 18

Goldshem-Ohm 2013 - inactivation deficient mutant -> movement leads to secondary conformational change exposes binding site for inactivating particle

Question 19

Docking site consists of

Answer 19

S4-S5 DIII and DIV

CTD S6 DIV

Question 20

Binding site has what type of residues?

Answer 20

Miyamoto 2001 - hydrophobic - allows phenyalanine at P1489 to interact with alanine in DIII S4-S5 and asparaganine DIV S4-S5

Question 21

What does hair-pin structure do?

Answer 21

Sirota 2002 - optimizes interaction etween IFMT and docking site - outtward movement occurs around a hinge comprised of glycine and proline

Question 22

What might underlie slow inactication

Answer 22

Capes 2013 - disable DIV S4 -> by introducing glutamine in the first 3 charge carrying residues -> slow entry and recovery from fast inactivated states

Question 23

CNS Nav’s are

Answer 23

Nav1.3 fetal nervous system tissue

1.1 , 1.2 and 1.6 in adults

Question 24

Where are 1.1 and 1.3 expressed and what does this indicate?

Answer 24

Soma of CNS neurons -> integrate synaptic impulses -> set AP initiaition and propagation to dendritic and axonal compartments

Question 25

Nav1.2

Answer 25

expressed in unmyelination neurons - conducts AP - westenbroek 1989

Question 26

Nav1.6

Answer 26

expressed in nodes of Ranvier in developing neurons - saltatory conduction - Boiko 2001

Question 27

How many alpha subunits?

Answer 27

Yu and Catterall 2003 - 10 distinct pore-forming alpha subunits, 9 of which are functional

Question 28

Nav1 contributes to

Answer 28

upstroke of AP

Question 29

Nav1.4

Answer 29

skeletal respiratory muscle ECC

Question 30

SCN4A mutants lead to

Answer 30

altered skeletal muscle excitability

• periodic paralysis
• congenital myopathy
• myasthenic syndrome

Question 31

Cardiac current needs

Answer 31

rapid depolarization

Question 32

Nav1.5 provides

Answer 32

fast, subsequent opening - ECC

re-open in plateau phase - late inward / persistent current -> viophysical proeprties of cardiac current

Question 33

Where else is 1.1 + 1.6 expressed

Answer 33

in adult PNS

Question 34

What is more expressed in PNS how was this found?

Answer 34

1.7, 1.8 and 1.9 -? cloned from sympathetic and DRG neurons