In the brain, neurons make use of both transient and enduring forms of synaptic transmission, using receptors that gate ion channels directly or second messengers. Synaptic actions by second messengers can close ion channels that are open at the resting potential, thereby decreasing the conductance of the membrane. In addition, second messengers can alter the biochemical state of nerve cells. For example second messengers cant alter gene expression to initiate persistent changes in function. Long lasting cellular modifications are extremely important in understanding memory formation.
Induction of a cascade of second messengers involves the recognition of specific extracellular signals (i.e., hormones, neurotransmitters, neuromodulators, growth factors, etc.) and activation of effectors. Thus, for instance, in the family of metabotropic receptors, that gate channels indirectly; recognition of the transmitter and activation of effectors are carried out by distinct and separate molecules. This family includes the a- and B- adrenergic receptors, serotonin, dopamine, and muscarinic acetyl choline receptors, receptors for neuropeptides and rhodopsin. Each receptor is coupled to its effector molecule by a guanosine nucleotide-binding protein (a G protein). Activation of the effector component requires the participation of several distinct proteins. Typically the effector is an enzyme that produces a diffusible second messenger, for example, cyclic adenosine monophosphate (cAMP), diacylglycerol, or an inositol polyphosphate. These second messengers trigger biochemical cascade either activating specific protein kinases (phosphate transferring proteins) that phosphorylate a variety of cellular proteins (thereby altering their activities), or mobilizing Ca ions from intracellular stores, thus initiating the reactions that changes the cells biochemical state. In some instances, the G protein of the second messenger can act directly on an ion channel.
Second messenger systems also exert actions on many target proteins other than voltage sensitive ion channels. A particularly interesting class of target proteins are the receptors for other transmitters. Second messengers can affect both types of neurotransmitter receptors - metabotropic and ionotropic. In this way, the action of one receptor can regulate its own effectiveness or the effectiveness of a receptor for another transmitter. Thus, for example, after prolonged exposure to its own chemical signal a receptor can become refractory to later applications of the same compound, a process called desensitization. Although many mechanisms produce diminished responsiveness, desensitization has been shown in several instances to result from protein phosphorylation.
Second messengers can regulate gene expression and thereby endow intercellular signaling with long lasting consequences. Recently, for example, a new kind of synaptic action has been discovered by which transmitters, acting through second messengers, phosphorylate transcriptional regulatory proteins thereby altering gene expression. Thus second-messenger kinases not only can produce previously existing proteins, but also can induce the synthesis of new proteins by inducing gene expression. This kind of synaptic action can lead to other changes, such as neuronal growth or synaptic remodeling, that can last days or even longer. Long lasting changes like this one are very important during development and might be instrumental in the formation of long term memory.
The same chemical transmitter can produce synaptic actions whit different time courses. A single
exposure to the transmitter can activate the c AMP second messenger system, which in turn
activates the cAMP dependent protein kinase that phosphorylates a K channel to produce a
synaptic potential that modifies neuronal excitability for a very short period of times; say,
minutes. However with repeated activation, the transmitter, acting through the cAMP dependent
protein kinase, also phosphorylates one or more transcriptional activator proteins that regulate
gene expression. This produces a protein that modifies the channel and results in a more
enduring alteration of the channel resulting in changes in neuronal excitability lasting days,
weeks or even more.
Anterograde and retrograde transport
The secretory functions in neurons are essentially similar to that in other cell types. However, given the extreme morphological polarity of nerve cells, there are important differences due to the complexity of the mechanisms involved in the trafficking of neuronal proteins. It is to be noted that cell bodies and nerve terminals are at considerable distance from each other. Consider for example, a spinal motor neuron that innervate muscles around the knee joint. The separation between cell body and nerve terminal imply the existence of a special transport system to bring newly formed membrane and secretory products form the Golgi apparatus to the terminal of the axon.There are three ways by which cellular components move within the axon: Fast anterograde (forward moving) axonal transport, slow axoplasmic flow and fast retrograde axonal transport. All newly synthesized membranous organelles within axons and dendrites are exported to the axon from the cell body by fast anterograde axonal transport. In warm blooded animals, organelles move at a rate of 400mm/day. At the nerve terminals the vesicle membranes are recycled many times, through exocytosis, for reuse in synaptic transmission. Membrane is constantly being replaced by new components arriving from the cell body. At a compensating rate, existing membrane components are returned form nerve terminals to the cell body, where they are either degraded or reused.
Fast anterograde transport depends on one or more of the filaments that make up the neuron's cytoskeleton. This axonal transport is based on microtubules that provide an essentially stationary track on which specific organelles move in a saltatory fashion. Fast anterograde transport is thought to depend on a microtubule- associated ATPase molecular complex known as kinesin.
Slow axonal transport is based on the slow axoplasmic flow. This transport carries proteins used to make up the fibrillar elements of cytoskeleton as well as the enzymes of intermediary metabolism that are formed on free ribosomes.
Fast retrograde transport occurs in the retrograde direction from nerve endings toward the cell body, returning materials from terminals to the cell soma either for degradation or for restoration and reuse. These materials are packaged in large membrane-bound organelles that are part of the lysosomal system. As in fast anterograde transport, particles move along microtubules. The motor molecule for fast retrograde transport is a form of dynein, which is a microtubule associated ATPase.