Cell Signaling and Ion Channels

Cell Signaling and Signal Transduction

• Membrane receptors, ligands, primary messengers, and secondary messangers all have roles in signal transduction cascades.
• Hormone molecules can trigger changes inside cells by affecting many molecules.
• Amplification and Attenuation control signals in signaling pathways.

Ion Channels

• Voltage-gated and ligand-gated ion channels have specific functions.
• Ion channels play a role in action potential and at the neuromuscular junction.
• Gated ion channels are regulated by a biological signal via a "gate".
• The gate allows the channel to switch between open and closed conformations.
• When open, ions diffuse following the electrochemical gradient.
• Gating factors include physical stimuli (mechanosensitive), ligand binding, voltage (membrane potential) and pH.

Voltage-Gated Channels

• Voltage-gated membrane channels change conformation in response to voltage fluctuations.
• A transmembrane peptide with a high charge density acts as a voltage sensor.
• Movement of the peptide (perpendicular to the membrane plane) responds to voltage fluctuations, which opens or closes the channel.

Membrane Potential

• Unequal charge distribution across a cell membrane results in the membrane potential.
• Na+-K+ ATPase establishes membrane potential.
• In the simplest case (membrane permeable to a single ion), membrane potential can be determined by the Nernst equation
• In living cells, concentrations and permeabilities of several ions (K+, Na+, and Cl-) govern membrane potential.
• Movement of ions causes redistribution of charge, with influx of + ion (or efflux of – ion) causing depolarization.

Voltage-Gated Channel Structure

• Voltage-gated channels have multiple subunits.
• Each subunit contains six transmembrane helices and an intracellular N-terminus.
• Helices 5 and 6 construct the pore.
• Helix 4 serves as the voltage sensor.

Intracellular N-Terminus

• The intracellular N-terminus of the K+ channel forms an inactivation domain.
• According to the ball-and-chain model, the channel is only open for a brief time interval.

Nerves

• Most neurons consist of a dendrite, a cell body, and an axon.
• Nerve impulses are transmitted via changes in membrane potential.
• Action potential is a rapid, temporary shift in membrane potential, triggered by ion channel opening.

Action Potential Phases

• Action potential has three phases:
  • Depolarization is when membrane potential becomes less negative and moves toward a positive charge.
  • Repolarization is when membrane potential returns to a negative charge.
  • Hyperpolarization is when membrane potential becomes more negative than the resting level.
• Action potential results from a strong inward flow of Na+ (depolarization) followed by a strong outward flow of K+ (repolarization).
• Action potentials propagate rapidly along the length of axons via electrical signaling as charge spreads.

Ligand-Gated Ion Channels

• Ligand-gated ion channels change conformation upon ligand binding.
• Ligands can bind extracellularly or intracellularly.
• Ligands do not get transported across the membrane.

Classes of Ligand-Gated Channels

• There are three classes of ligand-gated channels:
  • Cys-loop
  • Glutamate (P pore-loop)
  • ATP-gated P2X channels

Cys-Loop Channels

• Cys-loop channels have 5 subunits arranged around a pore.
• Each subunit has three domains:
  • Extracellular (ligand binding)
  • Transmembrane
  • Intracellular
• The acetylcholine nicotinic receptor is a Cys-loop channel.

Neuromuscular Junction

• Nicotinic receptors transmit neuronal signals from nerve cells to muscle cells.
• Acetylcholine releases from vesicles in the pre-synaptic neuron.
• Binding of acetylcholine opens channels to Na and K ions
• Acetylcholine (ACh) is a neurotransmitter formed from choline and acetylCoA.
• Acetylcholine is synthesized, stored, and released from cholinergic neurons.
• Acetylcholine releases into the synapse after an influx of Ca2+.
• Muscles contract after receiving signals from motor neurons.
• Acetylcholine degrades in the synapse cleft by acetylcholinesterase.
• Choline transports back into the pre-synaptic cell to be used for ACh synthesis.

Neuromuscular Blockers

• Neuromuscular blocking agents (NMBAs) are nicotinic receptor antagonists used with anesthesia.
• NMBAs induce paralysis.
• NMBAs are used for mechanical ventilation, tracheal intubation, and to relax muscles during surgery.
• NMBAs have no effect on the level of consciousness or ability to perceive pain.
• Nondepolarizing agents are competitive antagonists that bind to the acetylcholine receptor without opening the channel.
  • Prevent depolarization of the muscle cell and inhibit muscle contraction.
  • Effects can be reversed with acetylcholinesterase inhibitors.
• An example of a nondepolarizing agent is Vecuronium.
• Depolarizing agents mimic Ach, depolarizing the muscle and opening ion channels.
  • Depolarizing agents are resistant to degradation so opening of the channel persists.
  • Depolarized cells cannot respond to another stimulus, which halts the spread of nerve signal.
  • Depolarizing agents first cause muscle contraction (Phase I), then paralysis (Phase II).
• Succinylcholine is a depolarizing agent often used for rapid sequence intubation (RSI).
  • Succinylcholine has a rapid onset and a short duration.