Question

How can a neuron presynaptically regulate the activity of neuron? And is that true for gap functions?

Answer 1

A synapse is the point of connection between the endfoot of one neuron and the membrane of another. The word is derived from Greek and means "to fasten together." It is at synapses that one cell influences the activity of another.There are two broad categories of synapses: chemical synapses and electrical synapses. In mammals, chemical synapses predominate, but there is evidence of electrical synapses in some parts of our nervous systems, such as the retina of the eye. Electrical synapses are more commonly found in the brains of invertebrates. At a chemical synapse, the arrival of a nerve impulse at the endfoot of an axon triggers the release of a chemical agent,a neurotransmitter or neuromodulator substance, which falls upon the membrane of the postsynaptic cell. There it chemically induces an electrical response in the receiving cell, such as depolarization or hyperpolarization of the cell membrane. In contrast, at an electrical synapse, ionic currents transmit information from one cell to another directly; electrical synapses provide for a continuity of current flow between cells.The space between the presynaptic and postsynaptic membranes is the synaptic cleft. This gap is about 20-30 manometers wide and contains a large fluid component.The postsynaptic membrane is the third part of the synapse. This portion of the outer membrane of the receiving neuron is functionally specialized.. The structure of a synapse is clearly illustrated in Figure 5.2, which shows a special type of synapse between the endfoot of a neuron and a muscle fiber.Just as potassium dominates the resting potential and sodium controls the nerve impulse, it is calcium that regulates the release of a neurotransmitter into the synaptic cleft. However, researchers have just begun to understand the process by which an arriving action potential triggers the release of neurotransmitter and the role that calcium plays in that process.

Since the action potential is a complex phenomenon, involving the opening and closing of both sodium and potassium channels as well as changes of the membrane potential, more than one aspect of the action potential might control neurotransmitter release. An elegant approach to this problem was provided by Bernard Katz and Miledi (1967), who utilized two ion-specific neurotoxins- tetrodotoxin (TTX) and tetrathylammonium (TEA)- to rule out the effects of ionic movements in governing neurotransmitter release. TTX selectively blocks the voltage-regulated sodium channels of the axon. When it is applied to the presynaptic terminal, the action potential is not propagated, and, for that reason, no neurotransmitter is released by the endfoot. But if the endfoot is electrically depolarized, the chemical synapse continues to function in its normal fashion. This means that the operation of sodium channels is not necessary for neurotransmitter release.

Conversely, TEA selectively blocks the potassium channels of the axonal membrane. When administered together, TEA and TTX inactivate both the potassium and sodium channels of the membrane. Nevertheless, electrical depolarization of the membrane elicits a perfectly normal release of neurotransmitter substance into the synaptic cleft. This finding indicates that neither potassium nor sodium conductance plays any role in controlling the output of transmitter agent from the presynaptic element; transmitter release is triggered solely by depolarization of the membrane in the vicinity of the synapse.

In contrast, calcium does have a marked regulatory effect on the neurosecretory activity of the synapse. The amount of neurotransmitter released at a synapse varies directly with the concentration of calcium ions in the extracellular fluid. When extracellular calcium is reduced, the nerve impulse releases only a small amount of transmitter agent. Conversely, when the extracellular fluid is rich in calcium, The secretory output of the synapse is enhanced .appears that each action potential triggers the opening of calcium-selective channels at the synaptic membrane .During the depolarization portion of the action potential, voltage-dependent calcium channels at the synapse are activated. Positively charged calcium ions are electrically attracted to the negatively charged interior of the endfoot as the action potential is initiated. Furthermore, the interior concentration of calcium is very low, approximately 1/1000 of the extracellular concentration. Thus, there is a strong concentration pressure forcing the inward movement of calcium ions through the open calcium channels of the synapse.The molecular synapse mechanism by which entering ions facilitate transmitter release are not known I detail, but something like the following probably occurs: A neurotransmitter is packaged in small vesicles of membrane, each containing equivalent amounts of the transmitter substance. In some synapses, the contents of synaptic vesicles have been analyzed and found to contain something on the order of 1000 to 5000 molecules of neurotransmitter (Kuffler & Yoshikami, 1975). These packages are manufactured long before they are actually used, so external calcium levels cannot affect the amount of neurotransmitter within the vesicles.The influx of calcium during depolarization of the endfoot appears to activate a system of microtubules within the endfoot. The microtubules exert mechanical force and induce the movement of vesicles toward the presynaptic membrane. The vesicles then eject neurotransmitter into the synaptic cleft. In this way, calcium influx regulates the presynaptic release of neurotransmitter substances.
   When a nerve impulse reaches the end of an axon, the axon releases chemicals called neurotransmitters.

Neurotransmitters travel across the synapse between the axon and the dendrite of the next neuron.

Neurotransmitters bind to the membrane of the dendrite.

The binding allows the nerve impulse to travel through the receiving neuron

Gap junctions allow the exchange of ions, second messengers, and small metabolites between adjacent cells and are formed by two unrelated protein families, the pannexins and connexins. Mutations in connexin genes cause a variety of genetic disorders, implicating a critical role in tissue homeostasis. Association of congenital skin disorders to mutations in different connexins has underscored the importance of gap junctional communication in the skin and its appendages. Gap junction biosynthesis and assembly are strictly regulated and intercellular junctions have a short half-life of only a few hours . Most connexins are cotranslationally integrated into the endoplasmic reticulum membrane. The oligomerization of six connexins into a hemichannel is thought to occur in a progressive fashion starting in the endoplasmic reticulum and ending in the trans-Golgi network (Musil and Goodenough, 1993; Sarma et al., 2002; Laird, 2006). Connexons (hemichannels) are then carried to the cell surface via vesicles transported through microtubules, which fuse to the plasma membrane. These hemichannels can either form nonjunctional channels in unopposed areas of the cell membrane (see below) or diffuse freely to regions of cell-to-cell contact to find a partner connexon from a neighboring cell to complete the formation of intercellular channels.The continuous synthesis and degradation of connexins through these mechanisms may provide for the quickadaptation of tissues to changing environmental conditions. Unopposed hemichannels can also be functional under certain conditions, including mechanical and ischemic stress. Under these circumstances, open hemichannels are thought to facilitate the release of a variety of factors such as ATP, glutamate, and NAD+ into the extracellular space, generating different physiological responses. It is currently not known if active hemichannels become incorporated into gap junctions before degradation or follow a distinct recycling pathway.The concept that each gap junction channel is unique in terms of permselectivity is supported by a large number of studies. This specificity is well demonstrated in connexin-associated diseases, where loss of one isoform cannot be compensated for by coexpressed connexins. Beltramello et al.(2005) compared the permeability of wild-type Cx26 and deafness-associated Cx26 mutant V84L channels to IP3. Initially, they observed that both wild type and mutant channels were equally permeable to K+ ions. Then, they extended their experiments to test if the passage of IP3 between wild type or mutant channels was altered. Although mutant V84L channels were permeable to potassium ions, the IP3 transfer was impaired between the cells expressing the mutant protein.