Drug Targets - Ion Channel Flashcards
What are most abundant cations in the body?
sodium
potassium
calcium
What are the most abundant anions in the body?
chloride
phosphate
fluoride
What are the roles of ions?
Maintain osmotic pressure and hydration.
Facilitate nerve signal transmission and muscle function.
Support enzymatic activity and cellular processes.
What is a key feature of ion channels + details? (selective transmembrane pore)
Selective Transmembrane Pore (Molecular Sieve/Filter):
Ion channels act as selective filters, permitting the passage of specific ions based on their charge and size.
Sodium (Na⁺) channels: Do not permit potassium (K⁺) ions due to size and charge differences.
Potassium (K⁺) channels: Highly selective for K⁺ over Na⁺.
Ensures precise ionic balance and function in cellular processes.
What is a key feature of ion channels + details (specific sensors for gating)
Ion channels possess gating mechanisms controlled by conformational changes in the channel proteins.
These changes determine when the channel is open or closed, regulating ion flow.
What are the types of sensors or molecular switches?
1:Voltage-Gated Channels: Activated by changes in membrane potential (e.g., Na⁺ channels during action potentials).
2:Ligand-Gated Channels: Open upon binding of specific neurotransmitters or ligands (e.g., GABA or acetylcholine receptors).
3:Mechanosensitive Channels: Respond to physical stimuli like temperature or membrane stretch.
What is a key feature of ion channels + details (regulatory mechanisms)
Inactivation Control (Intrinsic):
Many ion channels have built-in mechanisms to switch to an inactive state after prolonged activation.
Abundance and Location:
The number of ion channels and their placement, such as in post-synaptic density, influences their activity.
Modulation by Cellular Components:
G-proteins, second messengers, and protein kinases can regulate ion channel activity, affecting their gating and responsiveness
What are the conformational states of ion channels?
1:Closed Confirmation: The ion channel is not permitting ion flow, blocking passage between the inside and outside of the cell.
2:Open-Active Confirmation: The ion channel is open, allowing ion movement across the membrane.
3:Open-Inactive Confirmation: The ion channel remains open but is unable to conduct ions, preventing further activity. This state is crucial for preventing overactivation.
What is the basic structure of the voltage gated ion channels?
*Composed of 4 subunits, which align together to form one functional ion channel.
*Each subunit contains 6 transmembrane helices (S1 to S6).
What are the key components of the voltage gated ion channels?
P-Loop:
Forms the selectivity filter or molecular sieve.
Aligns across subunits to create the transmembrane pore, allowing only specific ions to pass.
S4 Segment (Voltage Sensor):
Contains positively charged amino acids.
Moves up or down in response to changes in membrane potential, enabling the channel to open or close.
N-Terminus and C-Terminus are located intracellularly (inside the cell).
What is the inside and outside cell potential when: resting state
S4 Segments (Voltage Sensors) are positioned in response to the resting membrane potential.
Outside of the membrane: Positively charged (+).
Inside of the membrane: Negatively charged (-).
What is the inside and outside cell potential when: depolarisation
Membrane polarity reverses during depolarisation:
Inside becomes positively charged (+).
Outside becomes negatively charged
(-).
This change causes the S4 voltage sensors to shift, triggering the channel to open.
What can voltage gated ion channel be influenced by?
*other inorganic ions: nickel ions influence calcium channels
*neurotoxins: toxins from snakes, spiders and others can target channels
*drugs: synthetic drugs
What do toxins do to voltage gated ion channels?
Block ion flow.
Alter channel gating.
Cause overactivation or suppression of neural activity
What are the different types of calcium channels?
*T-Type channels
*N-type channels
*L-type channels
What are the details to T-type channels?
Found in pacemaker cells and peripheral nerves.
Associated with transient (short-term) calcium currents.
Therapeutic use includes epilepsy and neuropathic pain
What are the details to N-type channels?
Primarily located in neuronal synapses.
Regulate neurotransmitter release.
Targeted for chronic neuropathic pain management.
What are the details to N-type channels?
Predominantly found in cardiac and smooth muscle cells.
Play a crucial role in muscle contraction and neurotransmitter release.
Therapeutic interventions include drugs for hypertension, arrhythmias, and angina
What are the key roles of potassium channels?
Repolarisation: After the depolarisation phase of the action potential, potassium channels allow K⁺ efflux (movement out of the cell), helping the membrane potential return to its resting state.
Hyperpolarisation: The continued efflux of K⁺ ions can lead to more negative membrane potential, briefly surpassing the resting state.
What are some examples of neurotransmitters and their channels?
Acetylcholine: Channel: Nicotinic Ach Receptor (nAchR).
ATP: Channel: P2X.
5-HT (Serotonin): Channel: 5HT-3.
Glutamate: Channels: AMPA, NMDA, Kainate.
GABA (Gamma-Aminobutyric Acid): Channel: GABA-A receptors.
What are some examples of ligand gated cation channels?
Cation channels (Na+) – nicotinic Ach, glutamate, 5HT, P2X
» Depolarisation»_space; Excitatory
What are some examples of ligand gated anion channels?
Anion channel (Cl-): GABA»_space; GABAA ICl »_space; Hyperpolarisation»_space; Inhibitory
What are the advantages to allosteric drugs?
*offers a novel pharmacological options of “fine-tuning” receptor function
*intensify a weakened hormone/ NT signal caused by localised deficit
*Clinically safer drugs with enhanced selectivity and reduced liability for receptor tolerance and/or desensitation
