Neurotransmitters turnover rate

It is already evident that the turnover rate of a transmitter is only a crude measure of its release rate. Further limitations are that there is appreciable intraneuronal metabolism of some neurotransmitters notably, the monoamines. In such cases, turnover will overestimate release rate. Another problem, again affecting monoamines, is that some of the released neurotransmitter is taken back into the nerve terminals and recycled. This leads to an underestimate of release rate. Despite these drawbacks, studies of turnover rates uncovered some important features of transmitter release. In particular, they provided the first evidence for distinct functional pools of monoamines, acetylcholine and possibly other neurotransmitters a release pool, which could be rapidly mobilised for release, and a storage or reserve pool which had a slower turnover rate. 

Figure 4.1 Turnover of classical neurotransmitters. At normal rates of neuronal activity, endogenous stores of neurotransmitter are maintained at constant (steady-state) levels, indicating that the supply of new neurotransmitter (through synthesis) meets the demand (determined by release and metabolism). Consequently, the rate of the depletion (A) of the endogenous store of transmitter after inhibition of its synthesis indicates turnover rate and is described by the equation ...

In relation to the monoaminergic systems we observed that clobenpropit increased turnover rate of noradrenaline only in some brain regions (17), although histamine H3 heteroreceptors modulate the releases of noradrenaline, dopamine, and serotonin [23-26]. Thus, it appears that the contribution of histamine H3 hetero receptors on the modulation of monoaminergic neurotransmitters may be minor, just being similar to the cholinergic system. 

Synaptic integration often affects the rate of synthesis and degradation of a neurotransmitter or its rate of renewal or turnover. The turnover rate of a specific transmitter is the rate of renewal of that transmitter under steady-... 

Revuelta A, Cheney D. L, and Costa E (1981) Measurement of 7-aminobutync acid turnover rates in brain nuclei as an index of interactions between 7-aminobutyric acid and other transmitters, m Glutamate as a Neurotransmitter, (Dichiara G, and Gessa G. L, eds ), pp 169-181 Raven Press, New York Richardson, D L. and Scudder, C L (1976) Microwave irradiation and brain 7-aminobutyric acid levels in mice. Life Sa 18, 1431-1440 Robitaille Y., Wood P. L, Etienne P., Lai S., Fmlayson M H, Gauthier S, and Nair N P V (1982) Reduced cortical choline acetyl transferase activity in Gerstmann-Straussler syndrome Prog Neu-roPsychopharmacol. Btol. Psychiatr. 6, 529-531. 

Freeman M. E, Lane J D, and Smith) E (1983) Turnover rate of amino acid neurotransmitters in regions of rat cerebellum J Neurochem. 40, 1441-1447... 

Revuelta A. V, Cheney D L, and Costa E (1981) Measurements of y-Aminobutync Acid Turnover Rates in Brain Nuclei as an Index of Interactions Between y-Aminobutyric Acid and Other Transmitters, in Glutamate as a Neurotransmitter (Di Chiara G. and Gessa G L, eds ), Raven, New York... 

Acetylcholine serves as a neurotransmitter. Removal of acetylcholine within the time limits of the synaptic transmission is accomplished by acetylcholinesterase (AChE). The time required for hydrolysis of acetylcholine at the neuromuscular junction is less than a millisecond (turnover time is 150 ps) such that one molecule of AChE can hydrolyze 6 105 acetylcholine molecules per minute. The Km of AChE for acetylcholine is approximately 50-100 pM. AChE is one of the most efficient enzymes known. It works at a rate close to catalytic perfection where substrate diffusion becomes rate limiting. AChE is expressed in cholinergic neurons and muscle cells where it is found attached to the outer surface of the cell membrane. 

The rate of synthesis is similar for trace amines and monoamine neurotransmitters, however, trace amines undergo a more rapid turnover due to their higher affinity to MAO and the lack of comparable cellular storage. Thus, the tissue concentration of trace amines in the vertebrate central nervous system is estimated to be in the range of 1-100 nM, depending on the trace amine and brain area, in contrast to micromolar concentrations of classic monoamine neurotransmitters. 

The VMATs are also among the very few vesicular neurotransmitter transporters whose turnover number is known. At 29° C, they transport —5 molecules of serotonin per second and up to 20 molecules of dopamine (Peter et al., 1994). Since synaptic vesicles contain 5 to 20,000 molecules of transmitter and can recycle within at least 20 seconds (Ryan and Smith, 1995 Rizzoli et al., 2003), this rate has important implications for quantal size. At 5 molecules/second, the vesicle would contain only 100 molecules of transmitter after 20 seconds—if there were only one transporter per vesicle. Recent estimates suggest several transporters per vesicle (Takamori et al., 2006), but these might still not suffice to fill a rapidly cycling vesicle with monoamine unless the turnover was substantially higher at 37° C, where it is more difficult to measure transport accurately due to increased membrane leakiness. Indeed, the ability to determine the turnover of VMATs has been enabled by the availability of ligands to quantify the transporter and hence provide a denominator for measurements of transport. 

Investigators have employed a variety of neurochemical techniques to estimate neurotransmitter release from diencephalic DA neurons. The basis of these methods is that the release of DA is coupled to the rates of synthesis and metabolism of DA in terminals of DA neurons. Procedures that increase or decrease the neurotransmitter release from the DA neurons generally do not alter steady state concentrations of DA, but produce corresponding increases or decreases, respectively, in rates of synthesis, turnover and metabolism of this amine. The utility of various neurochemical procedures for estimating activity of diencephalic DA neurons has been discussed earlier (Moore, 1987a), and only reviewed briefly and updated in this section. 

The energy requirements of the neuron needed to maintain the Na" " and K+ gradients are pronounced. The maximal rate of ATP hydrolysis under conditions of maximal cation exchange has been estimated to be between 15 and 30% of the total hydrolysis of ATP within the neuron. In comparison, the combination of protein and lipid turnover and biosynthesis of neurotransmitters appears to require only 10% of the total ATP hydrolysis of the nerve. (The remaining hydrolysis occurs during active transport of other substances and for a variety of enzymatic reactions.)... 

In view of the recent results of Gullis Rowe (1975), who reported that the turnover of the hydrophobic chains of synaptosomal phospholipids was stimulated AJl )XJl/L0 by cyclic-AMP and putative neurotransmitters, the exchange of the hydrophylic heads (nitrogenous bases) of membrane phospholipids with externally added L-serine was examined in rat brain synaptosomes and synaptic membranes in the presence of cyclic-AMP or noradrenaline. This work was also prompted by some recent results of Lo Levey (1976), who showed that the rate of Ptd-Ser synthesis in heart slices, which certainly takes place by base-exchange (Kiss, 1976), is very efficiently stimulated by glucagon. 

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