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BSci Neuroscience: exam practice – guideline answers
Q1a. What is meant by an electrochemical gradient for Na+ ions, and how is it
established and utilized by excitable cells?
The Na+ ion concentrations inside and outside a neuronal membrane are different – about
10 mM inside, 110-140 mM. Non-equilibrium scenario. Distribution of ions is generated by
the Na-pump (on Na/K ATPase) utilizing metabolic energy in the form of ATP. Na+ ions from
inside the membrane are exchanged for K+ ions from outside, with a stoichiometry of 3/2.
Combination of Na pumping and low resting membrane permeability to Na+ ions means Na+
largely excluded from the intracellular compartment – helps balance the osmotic effects of
non-permeant intracellular protein (double Donnan equilibrium)
The neuronal membrane carries a resting potential that is largely explained by the resting K+
ion permeability of the membrane. Because of the non-equilibrium distribution of K+ ions, the
membrane potential is negative inside with respect to outside, ie it is much closer to the K
equilibrium potential than to the Na equilibrium potential.
The equilibrium potential for Na+ or for K+ ions is given by the Nernst equation:
• At 20 ºC, 58.2 log [out]/[in]
• At 37 ºC, 61.5 log [out]/[in]
• Thus a normal value of EK is negative and ENa is positive. For Na+, given the
internal and external concentrations of 10 mM and 110 mM respectively, and at 37
ºC, ENa = +64 mV. Can give alternative concentrations, so long as sensible
At the equilibrium potential for a given ion, the propensity for ions to move down the
electrical potential gradient across the membrane is exactly balanced by their propensity to
move in the opposite direction down their concentration gradient. Where the membrane
potential is different from the equilibrium potential, the driving force on the ion species is
given by the potential difference between the membrane potential and the reversal potential.
This is the ‘electrochemical’ gradient, and for Na+ ions, under normal circumstances, this will
drive an inward current. Therefore, under normal circumstances there is a chemical gradient
driving Na+ inwards, and also an electrical potential gradient driving Na+ inwards, and the
electrochemical gradient is the sum.
The electrochemical gradient for Na+ represents a form of stored energy that can be utilized
by excitable cells for the generation of impulses and long distance signalling through
propagated action potentials. Na+ channels incorporated in neuronal membranes selectively
allow Na+ ions to cross the membrane, and while they conduct briefly, the membrane
potential approaches closer to the Na+ equilibrium potential, giving the upswing and peak of
the action potential.
Q 1b. Referring to the Na+ channel subtypes normally expressed in peripheral sensory
neurones, in what ways are these channels functionally similar to each other, and in
what ways do they differ?
(this is a non-exhaustive list)
Na channel subtypes for which there is evidence of normal primary sensory neuronal
expression: NaV1.1, NaV1.2, NaV1.6, NaV1.7, NaV1.8, NaV1.9.
SIMILAR: Peripheral sensory neurones express a variety of Na+ channel sub-types. They
are similar in that they all comprise alpha and beta subunits. Alpha subunits in all tissues
show over 70 % homology in pore and gating regions.
SIMILAR: All voltage-gated Na channel sub-types, including all those in sensory neurones,
have alpha subunits based on the 4 domain repeat structure, with 4 S4 activation gates that
incorporate static +ve charge, and an intracellular inactivation gate with an IFM motif. The 4
domains coalesce to form a central aqueous pore.
SIMILAR: All Na channels expressed in sensory neurones can be found in several states,
including closed, open and inactivated, and they all normally generate inward currents when
activated (or journeying through the open state), that can contribute to neuronal excitation.
DIFFER: Na+ channels in peripheral sensory neurones can be pharmacologically
discriminated on the basis of their TTX sensitivity, the toxin pharmacology being critically
dependent on the amino acid sequence of each channel sub-type.
TTX tetrodotoxin, from the puffer fish, blocks within the channel vestibule close to the ion
selectivity filter. TTX-sensitive Na+ channels are blocked by single nM concentrations,
whereas TTX-resitant channels are resistant to 3 orders of magnitude higher concentrations.
DIFFER: the TTX-resistant Na+ channels in sensory neurones have slow activation and
inactivation kinetics, in comparison with the TTX-sensitive channel expressed in the same
cells. The TTX-resistant channel expressed in primary sensory neurones are NaV1.8 and
NaV1.9
DIFFER: NaV1.7, NaV1.8 and NaV1.9 have special roles to play in pain signalling. NaV1.8 and
NaV1.9 expression are markers for nociceptors
DIFFER: NaV1.6 is the channel that confers excitability at nodes of Ranvier. In A-fibres
NaV1.2 is expressed in the juvenile and is later replaced by NaV1.6
DIFFER: NaV1.8 is essential for pain signalling in the cold
Q 2. Discuss the statement “Glial function after injury – a double-edged sword”
Glia have good and bad roles; good roles largely restricted to normal functions and bad roles
most often occur after injury/inflammation
Should describe normal roles of astrocytes, microglia, oligodendrocytes and Schwann cells.
After injury/infection;
General bad role is in production &maintenance of pain – exemplified by lack of pain in neo
injury where glial immune response is weak.
Acute roles – mostly good; destruction of pathogens etc. Clearance of debris; Limiting size of
injury/infection e.g. glial scar
Schwann cells good roles – description of Wallerian degeneration & preparation for PN
regeneration; production of proinflam mediators (cytokines) – pain (bad) or protection of
injury site (good?)
Oligodendrocytes – bad roles production of inhibitory substances MOG, MAG, OMPG – that
prevent axonal regeneration; good role remyelination after CNS injury
Astrocytes – activated – good role provide structural support for degenerating structures.
Bad role production of proinflammatory substances, alterations in neurotransmitter
transporters. Glial scar formation becomes a barrier to regeneration. Roles in neuropathic
pain maintenance.
Microglia – good roles - scavenging “Pac-man” role clearing debrs away.Signalling to T cells
to help in immune response. Bad roles, contribution to neuropathic pain and with opioid
hyperalgesia… early roles in development of neuropathic pain
Extra points for details about signalling pathways & mechanisms.