Peptides are synthesized as large prepropeptides in the endoplasmic reticulum and are packaged into vesicles that reach the axon terminal by axoplasmic transport. While in transit, the prepropeptide in the vesicle is posttranslation-ally modified by proteases that split it into small peptides and by other enzymes that alter the peptides by hydroxy-lation, amidation, sulfation, and so on. The products released by exocytosis include a neurally active peptide fragment, as well as many unidentified peptides and enzymes from within the vesicles.

The most common removal mechanism for synaptically released peptides appears to be diffusion, a slow process that ensures a longer-lasting action of the peptide in the synapse and in the extracellular fluid surrounding it. Pep-tides are degraded by proteases in the extracellular space; some of this degradation may occur within the synaptic cleft. There are no mechanisms for the recycling of peptide transmitters at the axon terminal, unlike more classical transmitters, for which the mechanisms for recycling, including synthesis, storage, reuptake, and release, are contained within the terminals. Accordingly, classical transmitters do not exhaust their supply, whereas peptide transmitters can be depleted in the axon terminal unless replenished by a steady supply of new vesicles transported from the soma.

Peptides can interact with specific peptide receptors located on postsynaptic target cells and, in this sense, are considered to be true neurotransmitters. However, peptides can also modify the response of a coreleased transmitter interacting with its own receptor in the synapse. In this case, the peptide is said to be a modulator of the actions of other neurotransmitters.

Opioids are peptides that bind to opiate receptors. They appear to be involved in the control of pain information. Opioid peptides include met-enkephalin, leu-enkephalin, dynorphins, and ^-endorphin. Structurally, they share homologous regions consisting of the amino acid sequence Tyr-Gly-Gly-Phe. There are several opioid receptor subtypes: ^-endorphin binds preferentially to |x receptors, enkephalins bind preferentially to ^ and 8 receptors; and dynorphin binds preferentially to k receptors.

Originally isolated in the 1930s, substance P was found to have the properties of a neurotransmitter four decades later. Substance P is a polypeptide consisting of 11 amino acids, and is found in high concentrations in the spinal cord and hypothalamus. In the spinal cord, substance P is localized in nerve fibers involved in the transmission of pain information. It slowly depolarizes neurons in the spinal cord and appears to use inositol 1,4,5-trisphosphate as a second messenger. Antagonists that block the action of substance P produce an analgesic effect. The opioid enkephalin also diminishes pain sensation, probably by presynaptically inhibiting the release of substance P.

Many of the other peptides found throughout the CNS were originally discovered in the hypothalamus as part of the neuroendocrine system. Among the hypothalamic peptides, somatostatin has been fairly well characterized in its role as a transmitter. As part of the neuroendocrine system, this peptide inhibits the release of growth hormone by the anterior pituitary (see Chapter 32). About 90% of brain so-matostatin, however, is found outside the hypothalamus.

Application of somatostatin to target neurons inhibits their electrical activity, but the ionic mechanisms mediating this inhibition are unknown.

Nitric Oxide and Arachidonic Acid. Recently a novel type of neurotransmission has been identified. In this case, membrane-soluble molecules diffuse through neuronal membranes and activate "postsynaptic" cells via second messenger pathways. Nitric oxide (NO) is a labile free-radical gas that is synthesized on demand from its precursor, l-arginine, by nitric oxide synthase (NOS). Because NOS activity is exquisitely regulated by Ca2+, the release of NO is calcium-dependent even though it is not packaged into synaptic vesicles.

Nitric oxide was first identified as the substance formed by macrophages that allow them to kill tumor cells. NO was also identified as the endothelial-derived relaxing factor in blood vessels before it was known to be a neuro-transmitter. It is a relatively common neurotransmitter in peripheral autonomic pathways and nitrergic neurons are also found throughout the brain, where the NO they produce may be involved in damage associated with hypoxia (see Clinical Focus Box 3.2). The effects of NO are mediated through its activation of second messengers, particularly guanylyl cyclase.

Arachidonic acid is a fatty acid released from phospholipids in the membrane when phospholipase A2 is activated by ligand-gated receptors. The arachidonic acid then diffuses retrogradely to affect the presynaptic cell by activating second messenger systems. Nitric oxide can also act in this retrograde fashion as a signaling molecule.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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