Biochemistry Online: An Approach Based on Chemical Logic

Biochemistry Online





Learning Goals/Objectives for Chapter 9B:
After class and this reading, students will be able to

  • describe how a transmembrane ion gradient and nongated/gated membrane ion channels specific for given ions can give rise to a transmembrane electric potential across membranes
  • given ion concentrations and the electrical potential across a membrane, predict likely changes in the membrane potential and ion concentrations on the opening of specific channnels;
  • use the Goldman equation to predict transmembrane electrical potentials;
  • state difference between the communication across the neuromuscular junction and a synapse between two neurons;
  • state the difference between nongated and gated ion channels;
  • describe different ways to open/close gated ion channels
  • describe the immediate changes in the muscle cells when acetylcholine is released into the neuromuscular junction
  • describe the roles of stimulatory neurotransmitter receptors, voltage-gated Na+and K+ channels and the Na/K-ATPase  in the activation of a neuron;
  • explain the mechanism for selectivity of K+ over the smaller Na+ ion in the K+ channel;
  • briefly explain how membrane protein channels can be gated open by changes in transmembrane potential;

B9.  Excitatory  Neurotransmitters

Glutamate is a major excitatory neurotransmitter in the brain. Four types of glutamate receptors are found in the central nervous system.  They differ in the nature of ligands which bind to the receptor and which act as agonists. 

Figure:  Glutamate receptor ligands

Excessive amounts of glutamate are neurotoxic.  Three  of the receptor types are briefly described below:

Sobolevsky et al have recently analyzed the structure, symmetry and mechanism of the rat GluA2 receptor, a homotetramer, a bound competitive antagonist, ZK 200775.  GluA2, an AMPA type receptor, has structural similarities to an NMDA type receptor.  In order to determine the structure of the wild type GluA2 receptor, a model receptor polypeptide that was termed GluA2cryst (PDB# 3KG2) was crystallized.  Isolated GluA2 subunits were used to piece together a detailed model of rat GluA2 as it would exist in its natural membrane bound form.  The receptor has three main domains that are essential for its function.  The first is a large extracellular amino-terminal domain (ATD).  This domain serves as a guide for ligand binding in the next domain, the ligand-binding domain (LBD).  The ligand binding domain participates in agonist/antagonist competitive binding that regulates the gating of the ion channel.  The final domain is the transmembrane domain (TMD) that forms the ion channel for molecules to pass through the cell membrane. 

 The GluA2 receptor is shaped like a “Y” with the domains layered on top of each other.  The TMDs form the transmembrane section and base on the outside of the membrane.  The ATDs protrude outward like the “arms” of  a Y and the LBD is on top of the TMD.  This process gates the transmembrane channel as can be seen in Fig. 1.  Analysis of the crystallized protein uncovered a bound antagonistic ligand proving that the ligand binding occurs in a domain (LBD) rather than between domains, as was previously conceived. 

The authors studied the gating mechanism between the LBDs and TMDs by analyzing the change in symmetry that occurs when the gate is opened and closed.  When the gate is closed, the LBDs exhibit a two-fold symmetry and the TMDs four-fold symmetry.  When the ligand binds to the LBDs an abrupt structural change occurs creating four fold symmetry in the LBDs.  This transition was measured by calculating the r.m.s.d. of the alpha carbons between the subunits undergoing the structural change.  The TMDs also underwent a conformational change when ligand binding occured and ions travelled down the channel.  In order to accommodate the ion transfer, several subunits within the TMDs loosened their helix and provided an open pathway for the ion to travel in to the cytoplasm of the cell. 


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Archived version of full Chapter 9B:  Neural Signaling


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