| Acetylcholine (ACh) is the transmitter of the parasympathetic autonomic nervous system and of the sympathetic ganglia. Stimulation of the parasympathetic system produces effects that are broadly opposite to those of the sympathetic system, such as slowing of the heart rate, bronchoconstriction, and stimulation of intestinal smooth muscle. ACh also acts at neuromuscular junctions, where motor nerves contact skeletal muscle cells and cause them to contract. Apart from these roles, ACh may be involved in learning and memory, as neurons containing this transmitter also exist in the brain.
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| ACh is synthesized from choline by the enzyme choline acetyl transferase. After it is secreted into the synaptic cleft, it is largely broken down by acetylcholinesterase. The remainder is taken back up into the nerve cell by transporters similar to those for amines.
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There are two main classes of ACh receptors: nicotinic and muscarinic (see Chapter 39, Fig. 39.3). Both respond to ACh, but can be distinguished by their associated agonists and antagonists; they are quite different structurally and differ in their mechanisms of action:
- Nicotinic receptors are ionotropic. They bind nicotine
 and are found on ganglia and at the neuromuscular junction. When ACh or nicotine binds, a pore opens, which allows both Na+ and K+ to pass
through. Because the action of the ligand on the channel is direct, action is rapid; - Muscarinic receptors, responding to the fungal toxin, muscarine, are metabotropic. They are much more widespread in the brain than are nicotinic receptors, and are also the major receptors found on smooth muscle and glands innervated by parasympathetic nerves. Atropine specifically inhibits these receptors. There are several separate muscarinic receptors, differing in their tissue distribution and signaling pathways. As yet, no clear pattern has emerged as to their specific functions.
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| TETRAHYDROBIOPTERIN IS AN ESSENTIAL COFACTOR FOR DOPAMINE AND SEROTONIN SYNTHESIS |
| Tetrahydrobiopterin (BH4) is a member of the group of chemicals known as the pterins. Normally, BH4 is synthesized, via a number of enzymatic steps, from the precursor guanosine triphosphate. With regards to the central nervous system an adequate supply of BH4 is essential for tyrosine and tryptophan hydroxylase activities. When acting as a cofactor, BH4 is oxidized to quinonoid dihydrobiopterin (qBH2). BH4, under normal conditions, is regenerated from qBH2 by the enzyme, dihydropteridine reductase (DHPR). Several inborn errors of BH4 metabolism are now known. These can arise as a result of a failure of de novo BH4 synthesis or recycling by DHPR. If untreated, these patients have a number of severe neurological problems which include mental retardation, epilepsy and a movement disorder similar to that seen in Parkinson's disease. Following diagnosis, patients are treated by l-DOPA and 5-hydroxytryptophan, to bypass the metabolic block created by the BH4 deficiency. Following initiation of treatment, there is usually clinical improvement, resulting from the correction of dopamine and serotonin metabolism. However, BH4 is also the cofactor for all isoforms of nitric oxide synthase. There is now evidence to suggest that patients with BH4 deficiency also have an impaired ability to generate NO. Thus, research is now in progress to develop means to correct this impairment of the NO signaling pathway as well, for instance by gene therapy targeting the deficient enzyme of BH4 metabolism. Such an approach has the advantage of correcting the primary defect, i.e. the BH4 deficiency. |
| Clinically, ACh agonists, in common with acetylcholinesterase inhibitors, are used to treat glaucoma, an eye disease characterized by high intra-ocular pressure, by increasing the tone of the muscles of accommodation of the eye, and to stimulate intestinal function after surgery. On the other hand, when acetylcholinesterase is inhibited by
organophosphate insecticides or nerve gases, a toxic syndrome is caused by the resulting excess of ACh. There may be diarrhea, increased secretory activity of several glands, and bronchoconstriction. This syndrome can be antagonized by atropine, although longer-term treatment involves the use of drugs that can remove the insecticide from the enzyme, such as pralidoxime.
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