Muscarinic receptors postsynaptic

Acetylcholinesterase is a component of the postsynaptic membrane of cholinergic synapses of the nervous system in both vertebrates and invertebrates. Its structure and function has been described in Chapter 10, Section 10.2.4. Its essential role in the postsynaptic membrane is hydrolysis of the neurotransmitter acetylcholine in order to terminate the stimulation of nicotinic and muscarinic receptors (Figure 16.2). Thus, inhibitors of the enzyme cause a buildup of acetylcholine in the synaptic cleft and consequent overstimulation of the receptors, leading to depolarization of the postsynaptic membrane and synaptic block. 

Figure 6.2 Diagrammatic representation of a cholinergic synapse. Some 80% of neuronal acetylcholine (ACh) is found in the nerve terminal or synaptosome and the remainder in the cell body or axon. Within the synaptosome it is almost equally divided between two pools, as shown. ACh is synthesised from choline, which has been taken up into the nerve terminal, and to which it is broken down again, after release, by acetylcholinesterase. Postsynaptically the nicotinic receptor is directly linked to the opening of Na+ channels and can be blocked by compounds like dihydro-jS-erythroidine (DH/IE). Muscarinic receptors appear to inhibit K+ efflux to increase cell activity. For full details see text...

No overall reduction in cholinergic muscarinic receptors was found but recent studies with relatively specific ligands show a loss of presynaptic M2 receptors, in keeping with the loss of terminals, but no reduction in postsynaptic Mi receptors. Some acetylcholinesterase is found in plaques. 

M2 subtype modulates the amount of REM sleep. If postsynaptic muscarinic receptors of the M2 subtype contribute to REM sleep generation, then pharmacological manipulation of M2-activated signal transduction cascades would be anticipated to alter REM sleep (1.2 on Fig. 5.1). 

EEG slow waves. The differential EEG and ACh responses to dialysis delivery of AF-DX 116 (M2/M4) versus pirenzepine (M1/M4) supports the conclusion that, in B6 mouse, postsynaptic muscarinic receptors of the Ml subtype form one receptor mechanism by which ACh activates the EEG (Douglas et al, 2002a). The data summarized in Fig. 5.11 provide direct measures of G protein activation in basal forebrain and prefrontal cortex by muscarinic cholinergic receptors (DeMarco et al, 2004). The in vitro data of Fig. 5.11A indicate the presence of functional muscarinic receptors in regions of B6 mouse prefrontal cortex where in vivo microdialysis studies (Douglas et al, 2002a, b) revealed modulation of ACh release and EEG by pre- and postsynaptic muscarinic receptors (Figs. 5.9 and 5.10). 

Neurotransmission in autonomic ganglia is more complex than depolarization mediated by a single transmitter 190 Muscarinic receptors are widely distributed at postsynaptic parasympathetic effector sites 190 Stimulation of the motoneuron releases acetylcholine onto the muscle endplate and results in contraction of the muscle fiber 191 Competitive blocking agents cause muscle paralysis by preventing access of acetylcholine to its binding site on the receptor 191... 

Acetylcholine. Most of the acetylcholine in the basal ganglia is found in the striatum, as the neurotransmitter of the large spiny interneurons, which account for about 3% of all striatal neurons. Both muscarinic and nicotinic cholinergic receptors are found in the striatum. Postsynaptic muscarinic receptors may inhibit transmitter release from... 

Interaction of ACh with the postsynaptic ganglionic cell muscarinic receptor is responsible for slowly developing depolarization, the slow EPSP, which has a longer latency than the fast EPSP and a duration of 30 to 60 seconds. The slow EPSP is due to inhibition of a voltage-dependent K+ current called the M current, and inhibition of the M current involves activation of G proteins. At least five types of muscarinic receptors (Mj, M2, M3, M4 and M5) have been identified using functional studies and at least five subtypes (mj, m2, m3, rru, and m5) identified by molecular cloning techniques. The Mj receptor, which appears responsible for inhibiting the M current, can be blocked by atropine. 

The TCA drugs have lost their place as first-line therapy for depression because of their bothersome side effects (Table 33.2) at therapeutic doses and lethal effects in toxic doses. In addition to their presynaptic effects on the neuronal uptake of norepinephrine and serotonin, they block several postsynaptic receptors. They are potent cholinergic muscarinic receptor antagonists, resulting in symptoms such as dry mouth, constipation, tachycardia, blurred vision and urinary retention. Blockade of histamine receptors (Hi) often results in sedation and weight gain. Antagonism of aj-adrenoceptors in the vasculature can cause orthostatic hypotension. 

FIGURE 12—10. Acetylcholine (ACh) receptors. There are numerous receptors for ACh. The major subdivision is between nicotinic (N) and muscarinic (M) cholinergic receptors. There are also numerous subtypes of these receptors, best characterized for muscarinic receptor subtypes (Ml, M2, Mx). Perhaps the Ml postsynaptic receptor is key to mediating the memory functions linked to cholinergic neurotransmission, but a role for other cholinergic receptor subtypes has not been ruled out. 

Caulfield MP, Birdsall NJ (1998) International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50 279-90 Caulfield MP, Robbins J, Higashida H, Brown DA (1993) Postsynaptic actions of acetyl-choline the coupling of muscarinic receptor subtypes to neuronal ion channels. Progr Brain... 

Kloog, Y., Galron, R., Sokolovsky, M. (1986). Bisquartemary pyridinium oximes as presynaptic agonists and postsynaptic antagonists of muscarinic receptors. J. Neurochem. 46 767-72. 

---