lecture 5: Neurophysiology and Protein Transport

Na+ Channel Inactivation

• The Na+ channels have an automatic inactivation mechanism that causes them to reclose rapidly.
  • Inactivated State: The Na+ channel remains inactivated until the membrane potential returns to its initial negative value.
  • Inactivation Gate: A flexible loop connecting the third and fourth domains acts as a plug that obstructs the pore in the inactivated state.

Delayed K+ Channels

• Repolarization Requirement: Requires opening of delayed K+ channels.
  • These channels also respond to membrane depolarization but open during the falling phase of the action potential when Na+ channels are inactive.
  • K+ Outflow: When delayed K+ channels open, K+ rushes out of the cell until the resting potential is restored.

Propagation of Action Potential

• Action Potential Progression: Propagation occurs along the axon as voltage changes with Na+ channels and voltage-gated K+ channels.
  • Once initiated, the action potential travels only away from the depolarization site due to Na+ channel inactivation.

Transmission of Nerve Impulses

• Passive Spread: A neuron is stimulated when dendrites receive a depolarizing stimulus.
  • The depolarization spreads passively from the dendrite through the cell body to the axon hillock, where an action potential forms and propagates along the axon.

Myelination and Action Potential Speed

• Myelin Sheath: Insulates axons of many vertebrate neurons, significantly increasing action potential conduction speed.
  • Formation: Myelin is formed by glial cells that wrap their plasma membranes tightly around the axon.
  • Nodes of Ranvier: Interruptions in myelin where Na+ channels are concentrated, allowing action potentials to jump from node to node (saltatory conduction).

Saltatory Conduction

• Increases the speed of action potentials and conserves metabolic energy due to limited active excitation at nodes.

Chemical Synapses

• Signal Transmission: Neuronal signals are transmitted across synapses where presynaptic and postsynaptic cells are separated by a synaptic cleft.
• Voltage-Gated Ca2+ Channels: Action potentials cause these channels in the presynaptic membrane to open, leading to Ca2+ influx and neurotransmitter release via exocytosis.
• Transmitter-Gated Ion Channels: Neurotransmitters bind to these channels to induce electrical changes in the postsynaptic cell.

Neurotransmitter Removal

• After release, neurotransmitters are quickly removed from the synaptic cleft either by enzymatic destruction or reuptake by the presynaptic terminal or glial cells, ensuring signaling precision.

Excitatory vs. Inhibitory Neurotransmitters

• Excitatory Neurotransmitters: Generally open nonselective cation channels, allowing Na+ and Ca2+ influx, depolarizing the postsynaptic membrane.
  • Examples include acetylcholine and glutamate.
• Inhibitory Neurotransmitters: Open Cl- channels, making it harder for excitatory stimuli to depolarize the cell, thereby suppressing firing.
  • Examples include GABA and glycine.

Acetylcholine at Neuromuscular Junction

• Structure: Composed of five transmembrane polypeptides forming a transmembrane pore.
• Binding Mechanism: Binding of acetylcholine to the receptor induces conformational changes that open the channel, allowing cation influx.

Neuromuscular Transmission Overview

1. Nerve Impulse Arrival: Depolarizes the nerve terminal, opening voltage-gated Ca2+ channels.
2. Acetylcholine Release: Triggers release of acetylcholine into the synaptic cleft.
3. Binding to Receptors: Acetylcholine binds to receptors in muscle-cell membrane, causing cation channel opening and local depolarization.
4. Further Depolarization: Local depolarization opens voltage-gated Na+ channels, reinforcing the action potential.
5. Calcium Release: Activates voltage-gated Ca2+ channels in transverse tubules, leading to Ca2+ release from the sarcoplasmic reticulum into the cytosol.

Protein Transport Mechanisms

• Sorting Signals: Proteins have specific sorting signals that direct them to different cellular compartments.
• **Transport Methods:
  1. Transmembrane Transport: Direct transport via translocators.
  2. Gated Transport: Movement through nuclear pore complexes.
  3. Vesicular Transport: Transport via membrane-enclosed intermediates.
  4. Engulfment: Such as in autophagy, wrapping cellular components for transport.

Endoplasmic Reticulum (ER) Characteristics

• Diversity: ER is structurally diverse and involved in lipid and protein biosynthesis; it stores intracellular Ca2+.
• Rough vs. Smooth ER: Rough ER has ribosomes; smooth ER lacks ribosomes and is involved in lipid synthesis.
• Contacts with Other Organelles: Smooth ER makes contacts with mitochondria and plasma membrane for intracellular signaling and transport.

Microsome Isolation from ER

• Microsome Formation: During cell homogenization, the ER fragments into microsomes for study purposes; they retain protein translocation abilities.

Signal Sequence Recognition in Proteins

• Signal-Sequences and Translocation: Essential for directing ribosome to the ER for protein synthesis, with a signal peptidase trimming the sequence during translocation.

SRP (Signal Recognition Particle) Functionality

• Composition: Comprised of multiple polypeptides bound to RNA, guiding the ER signal sequence to its receptor at the ER membrane.
• Signal Sequence Binding: Holds the signal as it emerges from the ribosome, pausing translation temporarily until proper positioning is achieved.

Translocator Mechanism in Protein Transport

• The Sec61 complex forms a water-filled channel for polypeptide translocation across the ER membrane. It remains closed when idle, preventing leakage of ions until the signal sequence activates it for transport.