Lecture 5: Neurotransmitter Receptors - Structure and Function

Chapters 9, 10, 12 - The first principle to remember is that a transmitter's function is determined solely by the receptor.

There are two basic classes of receptors, ionotropic and metabotropic. These are activated by ligands -- transmitters. Thus, they are ligand gated.

The ionotropic receptor forms a channel become permeable when the receptor is activated by its respective transmitter. When inactive, it is impermeable to ions. When the transmitter dissociates from the receptor, the channel becomes impermeable again. They respond rapidly, and complete their actions rapidly.

The metabotropic receptor acts differently. When it is activated, it changes its conformation, its shape. This results not in a channel opening, but in binding to activating GTP-binding proteins (G proteins). The action outlasts the time of transmitter binding to the receptor. The action is slower in onset and of longer duration than that of ionotropic receptors. The actions can last from hundreds of milliseconds to hours, depending on the receptor.

Figure 9.1

Comparison of iontropic and metabotropic receptors. Ionotropic receptors bind the transmitter, under a change in shape, and become permeable to their respective ion(s) for the duration of the binding time. The receptor is a complex structure imbedded in the membrane.

The metabotropic receptor binds the transmitter and undergoes a shape change, but it then binds to a G-protein which has secondary actions internal to the neuron which result in longer lasting permeability or IMpermeability of a specific ion channel. The actions take longer because there are the enzymatic steps involved. It also can be an amplified action, as there are several steps along the way that can lead to enlargement of action.

Figure 9.3

The acetylcholine receptor is perhaps the best known iontropic channel. Its structure has been reconstructed and its molecular structure determined. Notice it has a funnel shaped pore that ends in a "gate" through which positively charged ions can pass when activated.

Figure 9.12

Diagram of the NMDA receptor, the N-methyl-D-aspartate receptor for glutamate. It is unusual in that it is both voltage gated due to the fact that Mg ions get 'stuck' in the pore, and it is ligand gated. It also has sites for other molecules that make it more or less sensitive.

There are numerous metabotropic receptors. We will not discuss them, except insofar as to indicate that they are extremely important, diverse, and their actions are slow to turn on and longlasting. They will come back repeatedly, but their structure is not of interest to us for now.

Chapter 10 - Intracellular Signaling

Figure 10.1

General overview of how G-proteins signal their actions after the receptor is activated. The receptor is coupled through a specific G-protein to different effectors, resulting in increased synthesis of second messengers and activation of protein kinases which mediate the further action of opening or closing the ion channels.

Figure 10.2

The G-protein is switched between two states. They are switched on by the transmitter activating the receptor, and switch themselves off after a given time delay. This is both a timer and an amplifier, as while the GTP is active, it produces changes in many effector enzymes. The longer its on, the more the signal is amplified.

Figure 10.5

Metabotropic receptors and their actions through G-proteins also allows for greater complexity with regard to convergence and divergence of signalling.

Figure 10.18

This convergence is further shown here with GABA, NMDA and DA receptors interacting.

Chapter 12 - Postsynaptic Potentials and Synaptic Integration

Here we see the actions of the different receptors in action.

Figure 12.1

The vertebrate stretch reflex - what it is and what it does in simplest form. Stretch of the muscle leads to activation of the stretch receptor which excites the muscle, causing it to contract. It also causes the activation of an interneuron which causes the inhibition of the antagonist muscle.

Figure 12.2

The responses of the neurons during the stretch reflex. Excitatory and inhibitory potentials, and action potentials are shown.

Figure 12.3

Recording of a single channel recording of an ionotropic receptor showing their properties and how they are measured with "patch-clamp" technique. The recording shown is an idealized recording of the current passed by opening and closing a single channel.

Figure 12.4

Above is the action of single channels. Below is the accumulated response of 1000 channels together.

Figure 12.5

The passage of current through a channel is voltage gated, and will reflect the balance of the ion and the ion's reversal potential. Thus, no current will flow through when the membrane potential is at the equilibrium potential for the ion, and the direction of the current will reverse when passed beyond the equilibrium potential.

Figure 12.7

NMDA and non-NMDA glutamate receptors and how they work. Non-NMDA receptors are iontropic and permeable to both Na and K ions. They are open briefly like all ionotropic receptors.

NMDA receptors open when activated with glutamate, but a Mg ion blocks the channel until there is sufficient voltage change to remove the Mg ion, and permit the flow of positive ions.

Figure 12.10

Fast and slow synaptic potentials. Notice the different time scales used in the two recordings! This is an idealized diagram in which one neuron activates a single fast EPSP via some ionotropic receptor type, and the second neuron activates a slow EPSP via the action of some metabotropic receptor type.

Figure 12.11

In the fast EPSP the receptor is bound to the channel and activation by transmitter opens the channel by virture of changing the shape of the receptor. The action is fast and short lived. In slow EPSPs the action of the transmitter is via a G-protein not directly coupled to the channel. Rather, the channel is acted upon as a consequence of second-messenger cascade. Here the channel is normally opened, but upon activation by the second messenger cascade, the channel CLOSES, blocking K, and causing an increase in the membrane potential.

Figure 12.12

Temporal and spatial summation. Two idealized neurons impinge upon a single neuron. When the inputs are separate, they do interact. However, if they follow closely enough, they will sum. Or if they lie close together enough and occur within the same time, they will add.

Figure 12.13

Modeling the integrative properties of a neuron and its dendrites. The modeling is a way of determining the accumulated action of many inputs to a neuron, all of which are fast PSPs, assuming no action potentials in the dendrites.