Transcript of Voltage-gated Sodium Channels XuelianMa. Introduction.
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- Voltage-gated Sodium Channels XuelianMa
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- Introduction
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- In1952 Hodgkin and Huxley demonstrated the role of sodium
channels in action potential electrogenesis and predicted many of
the properties of these channels Sodium channels play central roles
in electrogenesis in almost all types of neurons
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- Molecular structure A large subunits of 260 kDa and smaller
subunits of 30 40 kDa
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- The subunit is sufficient for expression of functional sodium
channels The subunits modulates the kinetics and voltage dependence
of sodium channel activation and inactivation modulates
localization of sodium channel.
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- The subunits four NaV subunits in total 1 and 3 are associated
non- covalently with subunits whereas 2 and 4 form disulfide bonds
with subunits
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- sodium channel properties are modulated in a cell-type specific
manner native neuronal background G616R variant of NaV1.7
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- Inherited Erythromelalgia ( ) L858H NaV1.7 mutation produce
hyperexcitability within DRG neurons and hypoexcitability within
sympathetic ganglion neurons. the selective expression of NaV1.8
within DRG neurons, and its absence within sympathetic ganglion
neurons
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- Figure 6. Excitability of sympathetic ganglion neurons is
reduced by erythromelalgia NaV1.7 mutation L858H but can be rescued
by coexpression of NaV1.8 A, suprathreshold responses recorded from
representative superior cervical ganglion (SCG) neurons
transf...
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- Two important principles The first is that the effects of ion
channel mutations on neuronal function are not necessarily
unidirectional or predictable on the basis of changes in channel
function per se; A single ion channel mutation can have divergent
functional effects in different types of neurons. The second is
that cell background and specifically the precise make-up of the
electrogenisome can shape the functional effects of an ion channel
mutation.
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- Nav channel neuronal distribution Sodium channel subunits are
expressed in different excitable tissues (Table1; Goldin, 2001).
NaV1.1, 1.2, 1.3 and 1.6 are the primary sodium channels in the
central nervous system. NaV1.7,1.8 and 1.9 are the primary sodium
channels in the peripheral nervous system. NaV1.4 is the primary
sodium channel in skeletal muscle, NaV1.5 is primary in heart.
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- The roles of different sodium channels in nociception
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- Nav1.3 Nav1.3 voltage-gated sodium channels have been shown to
be expressed at increased levels within axotomized dorsal root
ganglion (DRG) neurons and within injured axons within neuromas and
have been implicated in neuropathic pain.
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- The more hyperpolarized component of ramp current from Nav1.3
is more likely to be involved in altering threshold. The more
depolarized second component of ramp current may, in contrast, play
a role in inter spike interval pacemaking when neurons or their
axons are depolarized after injury.
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- NaV1.7 NaV1.7 activates in response to small slow
depolarizations close to resting potential so as to produce its own
depolarization The ability of NaV1.7 to boost subthreshold stimuli
increases the probability of neurons reaching their threshold for
firing action potentials. NaV1.7 is considered to be a threshold
channel
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- Nav1.8 Nav1.8 is relatively resistant to inactivation by
depolarization (Fig. 2A)and recovers rapidly from inactivation.
NaV1.8 thus produces repetitive firing in depolarized DRG neurons
Nav1.8 producing most of the inward current underlying the action
potential upstroke during repetitive firing
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- Nav1.7 and Nav1.8 function in tandem, with Nav1.7 amplifying
small depolarizations to bring the cell to threshold, and Nav1.8
producing most of the inward current underlying the action
potential upstroke during repetitive ring.
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- Nav1.9 NaV1.9, is characterized by very slow activation and
inactivation with a large overlap centred near resting
potential
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- this channel contributes a sodium conductance at rest that
modulates the excitability of DRG neurons Nav1.9
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- Multiple sodium channel subtypes participate in electrogenesis
in small DRG neurons NaV1.7(and NaV1.6 and/or NaV1.9 in some cells)
brings the neuron toward threshold (dashed line), NaV1.8 is largely
responsible for the overshooting action potential with minor
contributions of NaV1.1, NaV1.6 and NaV1.7 to the action potential
upstroke.
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- In 2005,Swensen & Bean Purkinje neurons from NaV1.6/ mice
in which sodium current density is reduced in the long term, where
an upregulation of calcium channels maintains excitability at close
to its normal level.
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- The firing properties of most neurons, are usually maintained
within a circumscribed range. A result of homeostatic regulation of
ion channel expression, post translational modification, and/or
interaction with binding partners or modulators. Changes in
expression of channel B can compensate for changes in expression of
channel A to maintain excitability within a particular range
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- These homeostatic regulation of intrinsic neuronal excitability
imply a need for an electrogenistat within excitable cells
Electrogenistat
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- Data Evaluation and Analysis
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- a
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- current versus voltage (I-V) curve
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- A number of important and useful parameters can be readily
derived from this plots, including: reversal potential,
voltage-dependence (rectification), activation threshold, as well
as overall quality of voltage-clamp
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- G = I/(Vm ENa), where G is conductance, I is peak inward
current, Vm is the membrane potential step used to elicit the
response ENa is the sodium reversal potential
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- -60mv -80mv 50mv Voltage-dependence of activation
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- Boltzmann distribution equation: GNa = GNa;max/{1+ exp[ (V 1/2
- Vm)/S ]} V 1/2 S
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- Boltzmann distribution equation: GNa = GNa;max/{1+ exp[ (V1/2 -
Vm)/S]} GNa is the voltage-dependent sodium conductance, GNa,max is
the maximal sodium conductance, V1 2 is the potential at which
activation is half- maximal, Vm is the membrane potential k is the
slope.
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- The kinetics of activation
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- -50mv 15mv -10mv -60mv Fast inactivation process
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- ** P < 0.01 vs no CRD group Boltzmann function: I = I max /
(1 + exp( V 1/2 V m )/ S ) V 1/2 S
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- INa = INa;max/{1+ exp[ (V1/2 - Vm)/k]} where INa,max is the
peak sodium current elicited after the most hyperpolarized
prepulse, Vm is the preconditioning pulse potential, V1 2 is the
half maximal sodium current k is the slope factor.
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- Steady state inactivation Inactivation kinetics
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- The kinetics of recovery from inactivation Time course of
recovery from fast inactivation 5ms 2nA -60mv -10mv Double pulse
protocol
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- I/Imax=1-exp(-t/tau)
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