ion channel diversity 2

Cavs convert electical signals directly into biochemical work in which areas

• synaptic transmission

• gene expression

• cell growth/survival

• muscle contraction

• neuroendocrine secretion

L type Cav 1.1-1.3

• high voltage activated

• muscle contraction - cardiac and smooth

• secretion from glands

P/Q type Cav 2.1

• high voltage activated

• transmitter release - largely in CNS 

N type Cav 2.2

• high voltage activated 

• transmitter release in PNS and CNS 

R type Cav2.3

• high voltage activated

• transmitter release 

T type Cav 3.1-3,3

• low voltage activated 

• excitability of cells 

• heart pacemaker cell activity 

difference between high voltage activated (eg L) and low voltage activated (eg T) type Cav

• no channels open at RMP

• as depolarization occurs around threshold T type channels open

• at higher voltage during AP L type will open

• around 30mV difference in activation

how can threshold for high voltage activated channels be variable?

• different beta and alpha 2 delta accessory subunits

alpha 1 subunit of Cav

• consists of 4 homologous domain

• each with S1-S6 transmembrane domain

• p loop inbetween S5 and S6

• 10 different isoforms

beta subunit of Cav

• modulates trafficking of alpha 1 subunit

• binds to large intracellular loop between domain I and II

which type of Cav have beta subunit associations

• high voltage 

• intracellular linking promotes trafficking 

alpha 2 delta subunit interaction with Cav

• low voltage association

• transmembrane protein 

gabapentinoids

• used in epilepsy and chronic pain

• reduced hyperexcitability 

• binds to alpha 2 delta subunit 

Dihydropyridines, Phenylalkylamines, Benzothiazepines, and Ziconotide

• binds to the alpha 1 subunit within I, II, III and IV transmembrane domain

• modifies open and closing of the channel 

L type channel blocker examples

1,4-dihydropyridines (DHPs) e.g. nifedipine – anti-hypertensive

Phenylalkylamines (PAAs) e.g. verapamil – anti-arrhythmic

Benzothiazepines (BTZs) e.g. diltiazem – anti-arrhythmic/hypertensive

where do only DHPs bind

transmembrane domain III

• anti hypertensive effect

where do DHPs, PAAs and BTZs bind

• transmembrane domain IV

• P loop 

• non competitively to distinct but overlapping sites

where do antagonists bind to L type Cav

• distinct regions of the alpha 1 subunit which control gating 

types of K+ channels

K_v (Delayed outward rectifiers + transient A-type current)

 K_Ca Small conductance (IK_Ca, SK_Ca)

                                            (Ca-activated)

 K_Ca Large conductance (BK_Ca)

 Kir (Inward rectifiers)

 K2P (two/tandem-pore domain)

function of K+ channels in excitable cells

• set rmp

• stabilise membrane potential to take it further away from firing threshold

• regulate AP repolarisation

• terminate periods of intense electrical activity 

• set time between repetitive AP firing 

• reduce potency of excitatory inputs on cells 

in which properties to heteromeric channels differ from parental

• biophysical

• pharmacological 

why are heteromeric channels easier to activate

• activated by smaller depolarisations

• more powerful repolarising current 

how are Kv channels blocked in the heart 

• quaternary ammonium ions eg TEA

how is AP interspike interval controlled

• by Kv channels

• interspike interval is short if current is small

• long if current is large 

calcium activated K+ channels 

• sensitive to both voltage and intracellular calcium conc

• binds to C terminal domain 

• couples with N type Calcium channel

effect of BKCa coupling with Cav2.2 (N type)

• mediates fast after hyperpolarisation in neurons

• inhibits neurotransmitter release

what are calcium actviated K+ channels blocked by

• TEA

• charybdotoxin 

function of SKCa and IKCa

• AP hyperpolarisation and after hyperpolarisation in neurons and muscle

• regulation of AP firing frequency

structure of SKCa and IKCa

• not positively charged so voltage insensitive

• alpha helical segments

• C terminal tail that allows direct binding of calcium and indirect binding of calmodulin 

what is SKCa blocked by

apamin

what is IKCa blocked by

TEA

what are inward rectifier K+ channels blocked by

• intracellular magnesium and polyamines 

• outward current increases with intracellular magnesium concentration 

function of polyamines to Kir

• block cytoplasmic side

• prevents potassium efflux at pos membrane potentials 

structure of Kir

• 2 transmembrane domains

when is there efflux of potassium

• when rmp is more positive than EK

physiological roles of Kir

• stabilise rmp near EK

• strong rectifiers close upon strong depolarisation of Vm

• weak rectifiers pass more outward current at depolarised Vm, reduce excitability