KV Channels Flashcards
What are potassium channels
- 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
Factors that can regulate potassium channels
- hormones and transmitters
- voltage across membrane
- concentration of calcium or STP in cytoplasm
- kinases and phosphatases
- G-proteins
Structure of 6-Transmembrane segment K channels
- 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
Role of Kv channels
- responsible for shaping AP
- two main types: inactivating and non-inactivating
Describe the ‘ball and chain’ model of inactivation of Kv channels
- ‘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’
How is ion selectivity determined
by carbonyl backbone groups of the TVGYG motif in P loop
Role of calcium-activated K channels
limit Ca entry and neuronal excitability
What are the 3 main subtypes of calcium-activated K channels
- Large conductance channels (BK)
- Maxi-K channels
- Intermediate (IK) conductance channels
- Small (SK) conductance channels
Role of SK channels
in neurons, responsible for presistent slow afterhyperpolarisation (AHP) observed after AP discharges
Role of Maxi-K channels
- in neurons, help shape APs and regulate transmitter release
- in smooth muscle, help regulate contractile activity and tone
Functional characteristics of Maxi-K channels
- 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
Structure of Maxi-K channel
- 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
Molecular characteristics of Maxi-K channels
- 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
What part of the Maxi-K channel determines Ca sensitivity
- 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
Physiological roles of Maxi-K
- 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
Maxi-K channels and VSM relaxation
- 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
Maxi-K channels and neuronal excitability
- 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
2 TM-domain potassium channels
one pore family consists of inward rectifiers which conduct K+ currents more in the inward direction than outward and help set RMP
4 TM-domain potassium channels
- 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
TREK1
- neuronal background cell
- two ‘P’ loops (K2P)
- channel activity controlled by numerous cellular factors
- highly expressed in human brain
K2P state at rest
K2P channels are constitutively open at rest and contribute to RMP
Ideal background current
follows GHK equation, is voltage-independent, amplitude immediately follows membrane potential. Is not rectifying
Opening of TREK1
- 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
Polymodal activation of TREK
TREK1 KO mice and the functions of TREK
- 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
Opening of TREK1 in presynaptic terminals
closes Cav channels and decreases release of neurotroxic glutamate
Opening of TREK1 in postsynaptic terminals
hyperpolarises the cell and increases NMDA receptor Mg2+ block, reducing exitotoxicity
K(IR)6.x channel
- 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
Functions of K(ATP) channels
- stress sensing e.g. skeletal, cardiac muscle, some neurons
- glucose sensing e.g. pancreatic beta cells, cetrain neurons in hypothalamus
Physiological roles of K(ATP) channels
- 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
K(ATP) physiological role in glucose-sensing cells
- 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
Pharmacology of K(ATP) channels
- 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
G-protein coupling to K+ channels
- 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
Long-QT syndrome (cardiac mutation)
- inherited genetic disorder characterised by prolonged or delayed ventricular repolarisation
- associated with reduced function of certain voltage-gated K+ channel genes
Epilepsy (neuronal mutation)
- certain forms of hereditary epilepsy associated with mutations leading to decreased expression/function of Kv channels
Hyperinsulinemia of infancy (metabolic mutation)
- bot sporadic and hereditary
- inappropriate enhanced insulin secretion occurs
- hypoglycaemia, coma, severe brain damage
- multiple mutations of K(ATP) channel
T2DM
- activating mutation in K(IR)6.2 associated with decreased insulin secretion from beta cells
