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Biomembranes > KV Channels > Flashcards

KV Channels Flashcards

1
Q

What are potassium channels

A
  • most diverse group of ion channels
  • contribute to control of cell volume
  • contribute to control of membrane potential and cell excitability
  • contribute to secretion of salts, hormones, and neurotransmitters
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2
Q

Factors that can regulate potassium channels

A
  • hormones and transmitters
  • voltage across membrane
  • concentration of calcium or STP in cytoplasm
  • kinases and phosphatases
  • G-proteins
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3
Q

Structure of 6-Transmembrane segment K channels

A
  • contains S4 voltage sensor and ‘P’ region
  • G(Y/F)G in P loop confers selectivity
  • voltage-activated Kv channels
  • hERG channels
  • calcium-activated K channels
  • KCNQ channels
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4
Q

Role of Kv channels

A
  • responsible for shaping AP
  • two main types: inactivating and non-inactivating
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5
Q

Describe the ‘ball and chain’ model of inactivation of Kv channels

A
  • ‘A’-type K channels display rapid inactivation following opening
  • inactivation is caused by first 20 AAs
  • inactivation forms compact hydrophobic/charged surface domain (ball)
  • 50-60 AA form the ‘chain’
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6
Q

How is ion selectivity determined

A

by carbonyl backbone groups of the TVGYG motif in P loop

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7
Q

Role of calcium-activated K channels

A

limit Ca entry and neuronal excitability

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8
Q

What are the 3 main subtypes of calcium-activated K channels

A
  • Large conductance channels (BK)
  • Maxi-K channels
  • Intermediate (IK) conductance channels
  • Small (SK) conductance channels
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9
Q

Role of SK channels

A

in neurons, responsible for presistent slow afterhyperpolarisation (AHP) observed after AP discharges

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10
Q

Role of Maxi-K channels

A
  • in neurons, help shape APs and regulate transmitter release
  • in smooth muscle, help regulate contractile activity and tone
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11
Q

Functional characteristics of Maxi-K channels

A
  • voltage-dependent (gated by depolarisation)
  • activation voltage is not fixed, but is dependent on intracellular Ca concentration
  • as Ca conc in cell increases, channel requires less electrical energy to open
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12
Q

Structure of Maxi-K channel

A
  • 7 TM structure, extra TM domain at N-terminal region results in exoplasmic NH2 terminus
  • Long COOH terminus -> important for function
  • Beta subunit binds to extracellular N terminus of Alpha subunit
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13
Q

Molecular characteristics of Maxi-K channels

A
  • alpha subunit encoded by single Slo gene
  • primary sequence is homologous to Kv channels
  • S0 is unique to Maxi-K channels
  • b1-b4 interact with alpha subunit -> alter sensitivity to Ca and voltage
  • S0/N-terminal domain is required for beta subunti modulation
  • alpha subunit primary sequence contains possible phosphorylation sites
  • abundant in mammalian CNS and smooth muscle
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14
Q

What part of the Maxi-K channel determines Ca sensitivity

A
  • tail domain
  • region between S9 and S10
  • contains series of negatively charged (D) residues
  • known as ‘calcium bowl’
  • mutations here affect high affinity sensing of calcium
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15
Q

Physiological roles of Maxi-K

A
  • important negative feedback system for calcium entry
  • contributes to AHP -> part of refractory period after AP firing
  • relax smooth muscle and balance effects of excessive vasoconstriction
  • loss of B1 subunit correlates with hypertension
  • provide mechanism for frequency encoding in hearing
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16
Q

Maxi-K channels and VSM relaxation

A
  • Ca release by CICR via ryanodine receptors causes local increase in intracellular calcium
  • rise in intracellular calcium activates BK channels, causing K efflux in a STOC (sponteneous transient outward current)
  • membrane hyperpolarises, closing CaV that gave initial depolarisation and contraction
  • vascular smooth muscle relaxes
17
Q

Maxi-K channels and neuronal excitability

A
  • present at high levels in axon terminals, somas and dendrites
  • generally have little influence on RMP but when activated by increased intracellular Ca, Maxi-K depresses excitability
  • Maxi-K blocking agents enhance transmitter release
  • Maxi-K ‘openers’ exist and reduce transmitter release
  • lack sensitivity to be used clinically
18
Q

2 TM-domain potassium channels

A

one pore family consists of inward rectifiers which conduct K+ currents more in the inward direction than outward and help set RMP

19
Q

4 TM-domain potassium channels

A
  • two pore family are weak inward rectifiers
  • most abundant class of K+ channels
  • act as ‘background’ channels and help set RMP
  • e.g. TWIK, TRAAK, TREK, and TASK
20
Q

TREK1

A
  • neuronal background cell
  • two ‘P’ loops (K2P)
  • channel activity controlled by numerous cellular factors
  • highly expressed in human brain
21
Q

K2P state at rest

A

K2P channels are constitutively open at rest and contribute to RMP

22
Q

Ideal background current

A

follows GHK equation, is voltage-independent, amplitude immediately follows membrane potential. Is not rectifying

23
Q

Opening of TREK1

A
  • signal integrators - respond to many inputs (mechanical deformation; internal pH reduction; heat) which increase channel opening and cause hyperpolarisation of RMP
  • inhibition of opening via phosphorylation at intracellular sites via PKC and PKA
  • various volatile and gaseous anaesthetic agents open TREK1
24
Q

Polymodal activation of TREK

A
25
Q

TREK1 KO mice and the functions of TREK

A
  • decreased sensitivity to various anaesthetics - channel contributes to cellular mechanisms of general anaesthesia
  • mice are more sensitive to brain ischemia and epilepsy - loss of neuroprotection from polyunsaturated fatty acids
  • mice are more sensitive to painful heat and mechanical stimulation
  • TREK1 plays a role in mood regulation as KO mice were less inclined to ‘give up’ when placed in stressful environment (anti-depressant)
  • TREK1 is an attractive target for development of new analgesics, neuroprotective agents, and antidepressants
26
Q

Opening of TREK1 in presynaptic terminals

A

closes Cav channels and decreases release of neurotroxic glutamate

27
Q

Opening of TREK1 in postsynaptic terminals

A

hyperpolarises the cell and increases NMDA receptor Mg2+ block, reducing exitotoxicity

28
Q

K(IR)6.x channel

A
  • widely explored as target for therapeutic agents
  • complexes with regulatory subunit to form the sulphonylurea receptor
  • SUR is a channel that is inhibited by intracellular ATP
  • 2 gene products for both subunits and various combinations provide diversity
  • K(ATP) channels act to couple cellular metabolism and electrical activity
29
Q

Functions of K(ATP) channels

A
  • stress sensing e.g. skeletal, cardiac muscle, some neurons
  • glucose sensing e.g. pancreatic beta cells, cetrain neurons in hypothalamus
30
Q

Physiological roles of K(ATP) channels

A
  • as stress sensors, they are closed under normal physiologic conditions and open under metabolic stress (e.g. hypoglycaemia, hypoxia/anoxia)
  • opening of K(ATP) channels results in hyperpolarisation of RMP
  • allows metabolically compromised cells to rest/recover
31
Q

K(ATP) physiological role in glucose-sensing cells

A
  • partially open under physiological conditions
  • contribute to cell RMP
  • increased glucose concentration increases intracellular ATP concentration and closes K(ATP)
  • inhibition of K(ATP) channels results in cell depolarisation
32
Q

Pharmacology of K(ATP) channels

A
  • target for therapeutic agents, both blockers/inhibitors and openers/activators
  • inhibitors: sulphonylureas (tolbutamide and glibenclamide), used in treatment of T2DM
  • activators: KCOs (cromakalim, pinacidil, diazoxide)
  • diazoxide is used to decrease insulin secretion
  • majority of KCOs have been developed to relax smooth muscle
  • KCOs may be useful as cardioprotective agents and neuroprotective agents
33
Q

G-protein coupling to K+ channels

A
  • can be direct e.g. cardiac muscle
  • GTP bound G-proteins cause K+ channels to open
  • activity of G-protein terminated by intrinsic GTPase activity of G-protein itself, converting GTP->GDP
34
Q

Long-QT syndrome (cardiac mutation)

A
  • inherited genetic disorder characterised by prolonged or delayed ventricular repolarisation
  • associated with reduced function of certain voltage-gated K+ channel genes
35
Q

Epilepsy (neuronal mutation)

A
  • certain forms of hereditary epilepsy associated with mutations leading to decreased expression/function of Kv channels
36
Q

Hyperinsulinemia of infancy (metabolic mutation)

A
  • bot sporadic and hereditary
  • inappropriate enhanced insulin secretion occurs
  • hypoglycaemia, coma, severe brain damage
  • multiple mutations of K(ATP) channel
37
Q

T2DM

A
  • activating mutation in K(IR)6.2 associated with decreased insulin secretion from beta cells

Biomembranes (12 decks)

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