Coupling Of Receptors To Intracellular Messengers

hydrolyzes the membrane phospholipid phosphatidylinositol 4,5-bis phosphate at the linkage between the glycerol backbone and the phospho-head group, liberating diacylglycerol (DAG) and inositol 1,4,5-tris phosphate. Both of these compounds serve as second messengers. DAG binds to and activates the downstream effector protein kinase C (PKC). IP3 binds to an intracellular receptor in the endoplasmic reticulum that is a calcium channel, leading to calcium mobilization from intracellular stores. Calcium of course is a pluripotent messenger in its own right and can activate a side variety of intracellular proteins and enzymes, including CaMKII.

Because second messengers are such powerful agents, regulation of their levels is carefully controlled. In cells specific enzymes for the breakdown of each of these messengers keep the levels of the compounds low in the resting cell. Phosphodiesterase is an enzyme that hydrolyzes cAMP into the inactive product 5'-AMP. Similarly, DAG lipase hydrolyzes DAG into its component parts, a glycerol molecule and two free fatty acids. DAG can also be inactivated by phos-phorylation to phosphatidic acid, via the actions of DAG kinase. IP3 is further metabolized by a very elaborate enzymatic system. IP3 can be both broken down by phos-phatases, leading ultimately to production of free inositol, or phosphorylated at additional sites by various kinases, leading eventually to the production of additional signaling molecules.

NMDA receptor activation locally, at present the specific molecular mechanisms that might operate in plasticity of this system have not been well defined.


Don't be misled by my use of the term "infrastructure." The term sounds very static and boring. In fact, the synaptic infrastructure that I am referring to is quite a dynamic place. The components of the synaptic infrastructure such as scaffolding proteins, cytoskeletal proteins, and cell surface adhesion molecules are now coming to be appreciated as important signaling components in the cell that respond rapidly and with great variety to extracellular and intracellular signals. I use the term "infrastructure" to describe these cellular components not because they are boring or immutable but rather because they have in common that they provide the underpinnings of the physical structure of the synaptic and dendritic regions.

However, there's a problem with studying these molecules. Most enzymes catalyze the conversion of one chemical species into another, Adenosine triphosphate (ATP) to cAMP, for example, and catalysis of this sort is fairly straightforward to identify, characterize, and study in detail. The molecules of the "synaptic infrastructure" that we will be discussing in this section by and large do not catalyze reactions of this sort. Many of them are not enzymes at all. Even where they are enzymes, the functional consequence of their catalysis is to cause a conformational change in another protein—they are allosteric modulators that achieve their effects by causing another protein to assume an altered shape in three-dimensional space. It is much more difficult to characterize these types of molecules because their effects do not lend themselves to easy quantification in vitro.

Futhermore, the tools necessary to do the block, mimic, and measure experiments that we have been discussing throughout the book are largely unavailable for these types of proteins at present. As an additional complication, think about what it means to do a "mimic" experiment on a protein whose functional role is to change from one conformation to another. An agent that locks the protein in any particular conformation disrupts the capacity of the protein to change conformation and thus to transduce a signal. An "agonist" can block function just as effectively as an antagonist.

The upshot of all this is that we are at a very early stage in studying these types of mechanisms—this is likely to be a rich area of future discovery. However, for right now, I am left mostly with the option of listing molecules that fit into this category, that have been implicated in LTP based on knockout or inhibitor studies. Placing them into a scheme for LTP induction is fairly speculative at this point, and in some cases the most that can be said is that they are known to interact with other proteins known to be involved in LTP. With these caveats in mind, I proceed with a brief listing of the more notable components of the synaptic infrastructure that have been implicated as contributing to LTP induction.

A. Cell Adhesion Molecules and the Actin Matrix

A prominent category of synaptic "adhesion" molecules are the integrins (40).

Integrins are cell surface molecules that transduce signals from the extracellular matrix to the inside of the cell. They are single-transmembrane-domain proteins that usually function as heterodimers of alpha and beta subunits. Knockout mice deficient in alpha5 and beta3 integrin exhibit hippocampus-dependent learning deficits and deficits in NMDA receptor-dependent LTP in area CA1 (41).

Integrins interact with a wide variety of intracellular effectors, three categories of which are clearly important to keep in mind in terms of LTP induction in general and regulating NMDA receptor function specifically (see Figure 3). First, integrins couple to src activation in many cells, and as we discussed in the first section of this chapter this is a mechanism for directly augmenting NMDA receptor function. Second, integrins couple to ras and via this mechanism can lead to ERK activation— this might play a role in K channel regulation (and regulating other effectors) as we discussed in the second section of this chapter. Finally, the prototype function of integrins is in regulating the actin cytoskeleton. This potential role of inte-grins has taken on special significance given recent findings by a number of laboratories, principally among them John Lisman's, that normal dynamic regulation of the actin cytoskeleton is necessary for LTP induction. Exactly how the actin cytoskeleton regulates LTP induction is unclear at present, but there will be many examples of candidate mechanisms that we will discuss in the rest of this section.

Integrin regulation of the actin cytoskeletal matrix is complex. One principal role is linking the extracellular matrix to sites of actin matrix adhesion on the cytoplasmic side of the membrane. Integrin cytoplasmic tails bind to alpha-actinin and talin, which in turn recruit actin binding proteins such as vinculin to the complex. This complex serves to anchor the cytoskeleton to the perisynaptic plasma membrane and synaptic zone.

FIGURE 3 Interactions among integrins and intracellular effectors that regulate NMDA receptor function. See text for discussion and definitions.

Integrins also regulate the small G proteins rho (ras homologue, first identified in Aplysia) and rac (which regulate actin dynamics)—this dynamic regulation of the actin matrix is especially appealing to consider in the context of activity-dependent changes in spine morphology. These types of rapid morphological changes in spine morphology have been studied quite elegantly by the laboratories of Gang-yi Wu, Richard Tsien, and Tobias Bonhoffer, to whose publications I refer you for further details. Consideration of integrin regulation of rho activity is especially appealing in this context because the classic role of rho is in regulating actin-myosin-based movement by activating myosin light-chain kinase. Another potential integrin effector in this context is the Focal Adhesion Kinase (FAK), which also serves to control cell morphology via the actin cytoskeletal matrix in many cells.

The actin cytoskeletal matrix may also contribute to NMDA receptor regulation in fairly direct ways. For example, actin microfilaments can serve as anchors for signaling components that affect the NMDA receptor directly. One example of this is actin filaments serving as the anchor for CDK-5, which as we discussed earlier can phosphorylate and activate the NMDA receptor. Also, A-potassium channels interact with the actin-binding protein filamin via their cytoplasmic C-terminal domain, and potassium channel beta subunits couple these channels to the actin cytoskeleton as well. These interactions certainly help localize A-channels appropriately in the dendritic spine. Perhaps more importantly, disruption of these interactions can cause attenuation of potassium channel function, and, as we discussed earlier, A-channel inhibition promotes increased membrane excitability and enhanced NMDA receptor function.

An additional interesting aspect of integrin function, one that is perhaps key in

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