In order for neuron communication to occur, the post-synaptic neuron must have receptor sites for the neurotransmitters released by the pre-synaptic neuron. Also, these neurotransmitters, by binding on to the receptors, must bring about a change in the post-synaptic neuron, namely an EPSP (excitatory post-synaptic potential) or an IPSP (inhibitory post-synaptic potential), which may or may not lead to an action potential triggering in the post-synaptic neuron.
EPSPs and IPSPs are produced in the post-synaptic neuron due to variations in either the Na+ or Cl- concentrations within the neuron. A change in concentration occurs when the protein channels which gate ion flow, permit Na+ or CL- to migrate across the cell membrane. The question now is, what causes the protein channels to open to Na+ or Cl-. In essence, there are three manners in which the ion flow can come about.
The simplest way in which neurotransmitter-receptor binding can cause the opening of the protein channels is when the receptor is located immediately on top of the protein channel. Once a neurotransmitter binds on to the receptor, it causes the protein channel to permit ion flow. Receptors can also be acting on protein channels in more indirect fashion, via a second messenger system. A second messenger system is characterized by a G Protein's inclusion in the transduction of "signals from the transmembrane receptors to intracellular effectors." (1) That means, the binding of a neurotransmitter to a receptor activates a G Protein, which causes the protein channels gating ion flow to open. For this, two general mechanisms exist. Before they can be explained, however, the structure and dynamics of the G Protein must be considered.
G Proteins are heterotrimic substances, i.e. they are composed of three subunits, alpha, beta and gamma. The alpha subunit of a G Protein is looked upon as the active subunit, as it binds GDP (guanine diphosphate) when it is inactive, but exchanges GDP for GTP (guanine triphosphat) when active (2) and acts as the "messenger" between the receptor sites and the effector. The beta and gamma subunits aid the alpha subunit to bind to membranes. They are otherwise considered the passive units of the G Protein, as they are dissociated form the alpha subunit when it executes its function in the neuron. After the alpha subunit has activated the effector, it returns to the resting state by cleaving the GTP, binding again to GDP, and reuniting with the betagamma dimer. (2,4,7)
A receptor mediating the opening of ion channels via a G protein is referred to as a G Protein coupled receptor. It is a component of a system that converts external signals into an intracellular second messenger system. (5) In the simple second messenger system, a neurotransmitter binds on to a receptor, the G Protein binds to the receptor and becomes activated, i.e. the alpha unit binds GTP instead of GDP and releases the other subunits. The alpha subunit then attaches to the protein ion channel and causes it to open, allowing ion flow. (2, 4, 7) The role of the G Protein in this case of signal transfer is very prominent and direct. Its function in the other version of the second messenger system is less direct. The G Protein in this case does not activate the protein channels in the membrane itself, but rather initiates a cascade of events which leads to the opening of the protein channels. As to explore this type of second messenger system, a representative system shall be explored, one involving adenylyl cyclase and cyclic adenosine monophosphat (cAMP).
The initial steps for this second messenger system are analogous to the steps seen in the one just described. A ligand binds to a receptor, a G Protein binds to the receptor, the GDP bound to the alpha unit is replaced by GTP, causing the unit to dissociates form the rest of the G Protein. (2,4,7) What is to follow differs form the simple second messenger system. Instead of binding to a protein channel, the alpha unit binds to another membrane protein, adenylyl cyclase. Adenylyl cyclase is responsible for converting adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Once the alpha unit latches on to adenylyl cyclase, this process is activated. (7,8) The cAMP then proceeds to activate yet another protein in the neuron, protein kinease. Protein kinease consists of two components, a regulatory unit and a catalytic unit. Normally, the catalytic unit is held in check by the regulatory unit. However, cAMP causes the units to dissociates. Hence, the active component, the catalytic unit, migrates to the protein channels in the membrane of the ion and causes them to open. Ion flow occurs, and EPSP or IPSP, respectively, are induced. (9) There are many more such second messenger systems, but effectively, they work similarly - a G Protein activates a cascade of changes in the neuron and as a result, ion channels open up. The insight we have now into the workings of G Proteins and ion channels are still very young and the work now possible because the missing link between receptors and protein channels (the G Protein) was found is being conducted thanks to Rodbell and Gilman, who established that link in the early 1990's. (2)
2) G-proteins and their role in disease--a student's report online.
2) Tertiary structure of a G protein
2) CELL BIOLOGY OF G PROTEINS--lab page of a Professor Bourne at UC San Francisco
5) dead link
6) Receptors and G Proteins slide
7) A description of G proteins
8) G-protein Activation and cAMP
9) Feldman, Meyer, Quenzer. 1997. Principles of Neuropsychopharmacology. Sinauer Associates, Inc. Sunderland, Massachussets.
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