Amino acids as neurotransmitters

Amino acids as neurotransmitters. The concentrations of glutamate and of its decarboxylation product y-aminobutyrate (GABA) are high in all regions... 

Bellomo M, Giuffrida R, Palmeri A, Sapienza S (1998) Excitatory amino acids as neurotransmitters of corticostri-atal projections immunocytochemical evidence in the rat. Arch Ital Biol 736 215-223. 

The transport of amino acids at the BBB differs depending on their chemical class and the dual function of some amino acids as nutrients and neurotransmitters. Essential large neutral amino acids are shuttled into the brain by facilitated transport via the large neutral amino acid transporter (LAT) system [29] and display rapid equilibration between plasma and brain concentrations on a minute time scale. The LAT-system at the BBB shows a much lower Km for its substrates compared to the analogous L-system of peripheral tissues and its mRNA is highly expressed in brain endothelial cells (100-fold abundance compared to other tissues). Cationic amino acids are taken up into the brain by a different facilitative transporter, designated as the y system, which is present on the luminal and abluminal endothelial membrane. In contrast, active Na -dependent transporters for small neutral amino acids (A-system ASC-system) and cationic amino acids (B° system), appear to be confined to the abluminal surface and may be involved in removal of amino acids from brain extracellular fluid [30]. Carrier-mediated BBB transport includes monocarboxylic acids (pyruvate), amines (choline), nucleosides (adenosine), purine bases (adenine), panthotenate, thiamine, and thyroid hormones (T3), with a representative substrate given in parentheses [31]. 

Cl dependence has been chiefly associated with amino acids which are not typical amino acids. These include taurine, -alanine, y-amino butyric acid (GABA), and betaine (Schon and Kelly, 1975 Kanner, 1978 Chesney, 1985 Turner, 1986 Kanner and Bendahan, 1990 Tiruppathi et al., 1992 Yamauchi et al., 1992). To a significant extent, some of these atypical amino acids (as well as glycine) are also neurotransmitters, although NaCl-coupled cotransport of these atypical amino acids also occurs outside the nervous system. The specificity for chloride is high. Of the anions tested (Cl-, Br-, I-, NO3, and glucuronate) as replacements, only sulphate has proved an effective substitute in a nominal way (25-50% of the activity in chloride see Turner, 1986). 

Evidence suggests that ketone bodies reduce epileptic seizures by changing the metabolism of certain amino acids (glutamate and aspartate) in the brain (Yudkoff et ah, 1997). These two amino acids are neurotransmitters, that is, they act as hormones that relay signals from one nerve to another adjacent nerve. 

Biochemical studies and retrograde labeling with D-[ H]aspartate provide strong evidence for an excitatory amino acid as transmitter in the corticofugal input to the spinal cord (Storm-Mathisen and Ottersen, 1988 Rustioni and Weinberg, 1989 Fig. 4). That Glu serves as a corticospinal neurotransmitter is further supported by the presence of high levels of Glu in corticospinal terminals in the dorsal horn (Valtschanoff et al., 1993). 

Cotman CW, Hamberger AC (1978) Glutamate as a CNS neurotransmitter properties of release, inactivation and biosynthesis. In Fonnum F (Ed), Amino Acids as Chemical Transmitters. New York Plenum Press, pp 379-412. 

Rouzaire-Dubois B, Scamati E (1987) Pharmacological study of the cortical-induced excitation of subthalamic nucleus neurons in the rat evidence for amino acids as putative neurotransmitters. Neuroscience 27 429-440. 

The absolute level of ammonia and its metabolites, such as glutamine, in the blood or cerebrospinal fluid in patients with hepatic encephalopathy correlates only roughly with the presence or severity of the neurologic signs and symptoms. y-Aminobutyric acid (GABA), an important inhibitory neurotransmitter in the brain, is also produced in the gut lumen and is shunted into the systemic circulation in increased amounts in patients with hepatic failure. In addition, other compounds (such as aromatic amino acids, false neurotransmitters, and certain short-chain fatty acids) bypass liver metabolism and accumulate in the systemic circulation, adversely affecting central nervous system function. Their relative importance in the pathogenesis of hepatic encephalopathy remains to be determined. 

Fig. 42.3. Interorgan amino acid exchange after an overnight fast. After an overnight fast (the postabsorptive state), the utilization of amino acids for protein synthesis, for fuels, and for the synthesis of essential functional compounds continues. The free amino acid pool is supported largely by net degradation of skeletal muscle protein. Glutamine and alanine serve as amino group carriers from skeletal muscle to other tissues. Glutamine brings NH4 to the kidney for the excretion of protons and serves as a fuel for the kidney, gut, and cells of the immune system. Alanine transfers amino groups from skeletal muscle, the kidney, and the gut to the liver, where they are converted to urea for excretion. The brain continues to use amino acids for neurotransmitter synthesis.

The nervous system consists of various cell types that are functionally interconnected so as to allow efficient signal transmission throughout the system (see Chapter 48). The cells of the central nervous system are protected from potentially toxic compounds by the blood-brain barrier, which restricts entry of compounds into the nervous system (ammonia, however, is a notable exception). The brain cells communicate with each other and with other organs, through the synthesis of neurotransmitters and neuropeptides. Many of the neurotransmitters are derived from amino acids, most of which are synthesized within the nerve cell. Because the pathways of amino acid and neurotransmitter biosynthesis require cofactors (such as pyridoxal phosphate, thiamine pyrophosphate, and vitamin BI2), deficiencies of these cofactors can lead to neuropathies (dysfunction of specific neurons within the nervous system). 

CgHjNOj, Mr 127.14, mp. 274°C (decomp.), [a] -288° (H2O) hydrochloride rap. 264°C, [a]g -90.1° (HjO). Non-proteinogenic amino acid first isolated from Rhodesian teak wood Baikiaea plurijuga (Faba-ceae) and later also from Caesalpinia tinctoria and red algae. B. inhibits the activity of glutamic acid as neurotransmitter. ... 

Microinjection tips constructed from capillaries drawn to very small diameters allow sampling from picoliter environments such as single cells or substructures within single cells. This technique has been used to study amino acids and neurotransmitters from single cells. Other novel injection techniques have been described in the literature. Commercial CE systems are available with thermostatted multiposition carousels for automated sampling. 

P-Endorphin. A peptide corresponding to the 31 C-terminal amino acids of P-LPH was first discovered in camel pituitary tissue (10). This substance is P-endorphin, which exerts a potent analgesic effect by binding to cell surface receptors in the central nervous system. The sequence of P-endorphin is well conserved across species for the first 25 N-terminal amino acids. Opiates derived from plant sources, eg, heroin, morphine, opium, etc, exert their actions by interacting with the P-endorphin receptor. On a molar basis, this peptide has approximately five times the potency of morphine. Both P-endorphin and ACTH ate cosecreted from the pituitary gland. Whereas the physiologic importance of P-endorphin release into the systemic circulation is not certain, this molecule clearly has been shown to be an important neurotransmitter within the central nervous system. Endorphin has been invaluable as a research tool, but has not been clinically useful due to the avadabihty of plant-derived opiates. 

Naturally Occurring Compounds. Many derivatives of iadole are found ia plants and animals where they are derived from the amino acid tryptophan. Several of these have important biological function or activity. Serotonin [50-67-9] (12) functions as a neurotransmitter and vasoconstrictor (35). Melatonin [73-31-4] (13) production is controlled daily by the circadian cycle and its physiological level iafluences, and seasonal rhythms ia humans and other species (36). Indole-3-acetic acid [87-51-4] (14) is a plant growth stimulant used ia several horticultural appHcations (37). 

---