Okay, well we're ready to shift gears now and talk about our metabotropic receptors. So again, these are receptors for neurotransmitters that are not ion channels, rather these receptors interact with a series of second messenger pathways within cells, that lead to a variety of postsynaptic effects. Perhaps the opening and closing of ion channels, but maybe a, a great diversity of other kinds of postsynaptic effects as well. So here's a typical example of a, a metabotropic receptor, also known as a G- protein coupled receptor, because the receptor itself Is a monomeric integral membrane protein, that is associated with g proteins on its cytoplasmic surface. When the receptor is activated by the neurotransmitter, these g protein systems then become active, and those g protein's then can then interact with the effector proteins, and those effector proteins can produce a variety of intercellular messengers, that potentially can gate some ion channels. So in this example, an ion channel does indeed open, following the binding of a neurotransmitter. So between the binding of the transmitter to a receptor, and the opening and closing of an ion channel in this example, are a series of metabolic reactions, and that takes time. So the metabolic steps are what accounts for the slower action of metabotropic receptors on postsynaptic conductances, relative to our ionotropic receptors where the effects are essentially instantaneous with the binding of a neurotransmitter to its receptor. So let's look at a couple of different examples. So the receptor itself is typically a monomeric integral membrane protein. But the intracellular second messenger systems related to G-proteins can be quite diverse. we have our more canonical heterotrimeric G-protein systems illustrated to the left, and so activation of G-proteins alpha, as well as the beta and gamma G proteins can go on and mediate a variety of postsynaptic effects, interacting with effector proteins. Some of which may produce second messengers themselves, others which may activate enzymes that can lead to the phosphor relation of target proteins in the activation of a variety of systems within postsynaptic cells. Other receptors for neurotransmitters are associated with monomeric G-protein systems such as the ras system. And activated Ras can go on and mediate a variety of postsynaptic effects itself. Here's some specific examples. our receptors for many of the bio-genetic means such as dopamine, norepinephrine, serotonin, they interact with G-protein coupled receptors. Illustrated to the left is the beta adrenegic receptor for Norepinephrine . It activates a gs version of the heterortrimeric g protein system, which leads to the activation of Adenylyl cyclase and an increase in the amount of cyclic amp that's produced within the cytoplasm. Cyclic AMP is an important second messenger system, that can then lead to the increased phosphorylation of target proteins. Glutamate binds not only to the ionotropic receptors, like the AMPA and NMDA receptor, but also to metabotropic receptors. Here glutamate is bonding to a receptor that activates gq proteins, and these can lead to the activation of phospholipase C, and the activation of other kinds of second messenger systems such as the ip3 pathway, and the diacylglycerol pathway. Again, leading to the phosphorylation or perhaps the dephosphorylation, of target proteins within the cell. And then lastly, we see that dopamine binds to metabotropic tropic receptors. We'll talk more about this when we talk about the circuitry of the basel ganglia. Dopamine is binding to a D2 receptor here, which interacts with a GI protein, in this case, leading to the inhibition of adenylylcyclase, and a reduction in the levels of cyclic A and P, and that leads to a decrease in protein phosphorylation in the target site. Now one benefit of the g protein coupled receptor family, is that there can be tremendous appli, amplification of the signal as these metabolic steps play out. So imagine activation of a single receptor leads to the production of a fairly large number of g proteins, so there's amplification in this step. Well, in the pathway for example following beta-adrenergic receptor activation, these g proteins can activate adenylyl cyclase enzymes, which then produce cyclic AMP. So another significant amplification step happens, where a large number of cyclic AMP molecules are derived from the activation of a smaller subset of adenylyl cyclase molecules. These cyclic AMP molecules, then can interact with protein kinases which leads to the massive phosphyorylation of numerous target proteins. So significant amplification Is the end result of activating a G protein coupled receptor. G protein coupled receptors can not only activate conductances in the post synaptic cell, they can also interact with transcription factors that can modify gene expression. And these kind of interactions, mediate the longest lasting effects of G protein coupled receptor activation. So there are pathways that follow the activation of heterotrimeric G protein system, that lead to the activation of regulatory elements, such as the CREB binding domain, in our genes. And activation of CREB, can lead to modification of gene transcription. similar CREB modifying pathways can converge upon the same machinery within the nucleus, through different pathways. Here's an example of a Ras mediated pathway also activating CREB. sudden rises in intracellular calcium, likewise, can interact with calmodulin independent kinases to activate CREB. so there may be a variety of ways that we can influence the transcription of the genome, based on the interactions that are happening out at the plasma membrane of a neuron. And g protein coupled receptors, are one important means for doing so. If we look at the molecular structure of g protein coupled receptors, what we find are typically seven trans membrane domains. these seven trans membrane domains are characteristic of this gene family. And so we now know that they encode a variety of G-protein coupled receptors, that show up in some surprising places. So what they have in common, is that they are a monomeric protein. There is an extracellular domain, which typically includes an interminus and a site for the binding of a neurotransmitter. in this example what we're seeing is the muscerinic variety of acetylcholine receptor. there is of course a cytoplasmic side of the molecule that interacts with the G proteins, so we expect to see that as well. And again, the defining feature are these seven trans membrane domains that run through the plasma membrane. So, as I said, there are a variety of G proteins, and they show up in some surprising places. We'll find G proteins, for example, involved in sensory transduction, in some of our special sensory systems, including the olfactory system, and even the visual system. So the transduction of photons into electrical energy, requires the activation of the G-protein coupled receptor system. So there's a variety of metabotropic receptors for a large family of small molecule neurotransmitters as well as for our peptide neurotransmitters. And, the complexity of this system is just now beginning to be appreciated. What's important for you to take away is the idea that the metabotropic receptor's give rise to these more slowly evolving, but potentially much more, long lasting effects of the binding of a transmitter to it's receptor. So now that we've talked about the diversity of receptors that are present that interact with the neurotransmitters, I think you can understand why we cannot judge the physiological effect of a neurotransmitter, by only knowing something about thee identity of the transmitter. And the kind of chemical structure of that transmitter. No, that's not enough. We have to know about the receptor in order to understand the physiological effect. And that receptor might be an ionotropic receptor emediating a fast effect on a postsynaptic conductance, or it might be a metabotropic receptor emediating a slowly evolving effect that impacts a post-synaptic conductance, but could also alter gene transcription, and thereby have a long lasting effect on that postsynaptic cell. Well, we're going to come back to some of these themes. And we will return to our metabotropic receptor family as I mentioned they show up in some pretty surprising places. We'll discover G protein coupled receptor systems, in our special sensory pathways such as our olfactory system, and in our visual system. and perhaps you'll be surprised to discover that the act of seeing, requires the activation of a G protein coupled receptor, very much like the same kinds of receptor structures we've just been looking at. So stay tuned for that. But meanwhile, now that we understand some of the basic molecular and cellular mechanisms that are responsible for chemical neurotransmission, we're ready to talk about the integration of electrical signals in a postsynaptic cell, and then that will allow us to talk more about synaptic plasticity, and how the effectiveness of the synapse can be altered by its very use. So, I look forward to having those discussions with you in the next few tutorials.
