Week 24 - drug targets, ion channels Flashcards
Most abundant ions in the human body - cations (+)
Sodium (Na⁺): Predominantly found in extracellular fluid, essential for maintaining fluid balance and nerve transmission
Potassium (K⁺): Major intracellular cation, crucial for muscle contractions and heart function
Calcium (Ca²⁺): Vital for bone structure, muscle contractions, and blood clotting
Most abundant ions in the human body - anions (-)
Chloride (Cl⁻): Key extracellular anion, important for maintaining osmotic balance and acid-base regulation
Phosphate (PO₄³⁻): Found in bones and cells, involved in energy storage (ATP) and acid-base buffering
Fluoride (F⁻): Found in small amounts, important for dental health and bone strength
Roles of ions
-Maintain osmotic pressure and hydration
-Facilitate nerve signal transmission and muscle function
-Support enzymatic activity and cellular processes
Key features and properties of ion channels
-Selective transmembrane pore (molecular sieve/filter)
-Specific sensors for gating (open and close)
-Regulatory mechanisms
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
Specific sensors for gating (open and close)
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
Types of sensors or molecular switches:
-Voltage-gated ion channels
-Ligand-gated channels
-Mechanosensitive channels
Voltage-gated channels
Activated by changes in membrane potential (e.g., Na⁺ channels during action potentials)
Ligand-gated channels
Open upon binding of specific neurotransmitters or ligands (e.g., GABA or acetylcholine receptors)
Mechanosensitive channels
Respond to physical stimuli like
temperature or membrane stretch
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
Physiological importance (regulatory mechanisms)
These regulatory mechanisms ensure proper ion flow, maintaining cellular homeostasis and preventing abnormal activities like over- excitation or prolonged inactivity
Conformational states of ion channels
Closed confirmation: The ion channel is not permitting ion flow, blocking passage between the inside and outside of the cell
Open-active confirmation: The ion channel is open, allowing ion
movement across the membrane
Open-inactive confirmation: The ion channel remains open but is unable to conduct ions, preventing further activity - this state is crucial for preventing overactivation
Voltage-gated ion channel - basic structure
(Sodium, potassium and calcium channels)
Basic structure: Composed of 4 subunits, which align together to form one functional ion
channel -> each subunit contains 6 transmembrane helices (S1 to S6)
Voltage-gated ion channel - key components
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 (start of amino acid) and C-Terminus (end of amino acid) are located intracellularly (inside the cell)
Functional Assembly: The 4 aligned subunits form a complete channel with distinct
ion selectivity and gating properties
Importance: These channels regulate ion flow critical for processes such as nerve impulse transmission, muscle contraction, and cellular signalling
6 transmembrane helices -> Amino acid dips 6 times through the transmembrane (phospholipid membrane)
Voltage-gated ion channels: voltage-sensing
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 (-)
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
ION FLOW:
Once the channel opens, sodium ions (Na⁺) flow through the channel from the outside to the inside of the cell -> this ion movement contributes to the action potential
Action potential
The movement of Na⁺ ions results in a spike in the membrane potential, depicted in the action potential curve
->The channel will eventually return to its resting state once the depolarisation is complete
Functional significance:
Voltage-gated ion channels are critical for propagating electrical signals in excitable tissues such as neurons and muscles
Voltage-gated ion channels: inactivation loop
Regulatory Mechanisms: Inactivation is built-in: it is an intrinsic property of the ion
channel -> the inactivation loop ensures rapid channel closure to control ion flow and maintain proper cellular function
Resting (closed confirmation) -> inactivation loop
The ion channel is closed, maintaining the resting membrane potential:
->Outside of the membrane: positive charge (+)
->Inside of the membrane: negative charge (-)
->The inactivation loop (illustrated as the “ball and chain”) is not engaged
Depolarised (open-active confirmation) - inactivation loop
Depolarisation occurs:
->Inside becomes positively charged (+)
->Outside becomes negatively charged (-)
The channel opens, allowing ion flow (e.g., Na⁺) across the membrane
Inactivation (open-inactive confirmation) - inactivation loop
After a brief period of opening, the inactivation loop (ball and chain mechanism) blocks the channel pore from the intracellular side -> this prevents further ion flow, even if the channel remains open structurally
Voltage-gated ion channel function and drug action
INORGANIC IONS: Certain inorganic ions act as modulators by either enhancing or inhibiting
the ion channel’s activity
NEUROTOXINS: Toxins from venomous creatures like snakes, spiders, and others can directly target voltage-gated ion channels
->These toxins often:
-Block ion flow
-Alter channel gating
-Cause overactivation or suppression of neural activity
DRUGS: Synthetic drugs are designed to interact with voltage - gated ion channels for therapeutic purposes
e.g., Local anaesthetics block sodium channels to prevent pain signals // Calcium channel blockers (e.g., for hypertension) reduce calcium influx
Neurotoxin action
Neurotoxins block sodium channels in all conformational states -> closed, open, and inactivated
This blockade prevents sodium ions from flowing into the cell, leading to disrupted neural signalling and paralysis
Lidocaine mechanism
Lidocaine -> a local anaesthetic - prefers to bind to sodium channels in their open or inactivated states
->This mechanism is described as “use dependency”:
-Lidocaine’s action increases with higher frequency or repetitive channel activation
->It blocks the flow of sodium ions, disrupting the nerve signal
transmission
By targeting sodium channels during their active or inactivated states, lidocaine effectively blocks pain signal transmission
->This property makes it a widely used anaesthetic in clinical settings
Three types of calcium channels
(Differ in sensitivity and conductance)
1) T-Type Channels
2) N-Type Channels
3) L-Type Channels