electrical signalling in neurons 2

PNF

gating behaviour of voltage-dependent channels

• rapid activation of Nav channels gives rise to transient depolarising signal

• opening of Kv channels decreases rate of repolarisation, shortening AP duration

• faster activation of Kv, shorter AP duration

complex neuronal firing patterns

Kvs differ in voltage-dependence of activation/deactivation and gating kinetics. combined activity of different Kvs determins firing patterns

regulating K+ channel properties

modulated by chemical messengers, as their behaviour changes so does firing properties of neuron.

e.g. noradrenaline effects cAMP, changing K+ channels to cause chain of APs rather than one

changes in firing patterns regulates behaviour

hypothalamic neurons: changes in Kv4 channel affected feeding behaviour in mice

pharmacological blockers

tetrodotoxin → blocks inward Na+ current

tetraethylammonium → blocks outward K+ current

toxins

in animals commonly contain peptide toxins that target ion channels, inactivating prey. used to identify variety of Kv, Nav and Cav channels

diversity of Kv channels

most diverse ion channel family. encoded by multiple genes. divided into subfamilies based on amino acid sequence similarity. individuals in families are structurally similar.

common Kv channel structure

one domain with 6 transmembrane regions. channel has 4 subunits assembles into a tetramer. auxiliary subunits assemble with main subunits and alter channel properties.

subunit composition of Kv channels

affects their gating properties.

mixing subunits from same subfamily increases diversity

differences in Kv functions

Kv1 and 4 → interval between AP firing

Kv2 and 3 → duration of AP

differences in expression patterns

Kv1.1 and 1.3 → small clusters either side of nodes of Ranvier

Kv4.2 → main channel present on dendrites

Kv2.1 → around soma and beginning of dendrites

Nav1.1, 1.2 and 1.6 → nodes of Ranvier, throughout soma and dendrites

immunostaining

enables visualisation of different targeting of Kv channels, e.g. immunofluorescence labelling - shows differences in expression patterns in a neuron

how does Kv channel spread relate to their roles

• voltage gated ion channels involved in initiation propagation of the AP are targeted to axon hillock and nodes of Ranvier

• if involved in NT release, targeted to pre-synaptic terminals

• if involved in integration of synaptic inputs, targeted to dendrites

regulation of surface expression and targeting of Kv channels

by auxiliary proteins and phosphorylation. roles include:

• protein promoting surface expression of Kv channels

• phosphorylation of channels to up or down-regulate expression

• proteins can be targeted to post-synaptic density, target Kv channels to post-synaptic sites

Kv1 channels at pre-synaptic terminal

regulate NT release. less Kv1 open, longer AP duration, more Ca2+ enters, more NT released

functional domains of VG channels

• 6 membrane spanning segments (S1-S6)

• S4 is voltage sensor

• S5—P-loop—S6 is the pore, highly conserved between channels

similar between Nav and Kv

opening of channel pore

coupled to outward movement of S4 from depolarisation sensed by S4 amino acids. this is coupled to movement of gate at cytoplasmic side of S6, opening pore.

reverse happens at hyperpolarisation

ion channelopathies

diseases caused by mutation in a gene that encodes an ion channel subunit. alters function of channel, can be GOF or LOF

Nav channel mutations

SCN1A most commonly associated with epilepsy, this gene encodes Nav1.1, which is widely expressed in CNS in inhibitory GABAergic interneurons. reduction of function causes imbalance between inhibition and excitation.