Second messengers muscarinic receptors

The GABAB-receptors, the muscarinic M2- and IVU-receptors for acetylcholine, the dopamine D2-, D3-and D4-receptors, the a2-adrenoceptors for noradrenaline, the 5-HTiA F-receptors for serotonin, and the opioid p-, 8- and K-receptors couple to G proteins of the Gi/o family and thereby lower [1] the cytoplasmic level of the second messenger cyclic AMP and [2] the open probability ofN- andP/Q-type Ca2+ channels (Table 1). The muscarinic Mr, M3- and M5-receptors for acetylcholine and the ai-adrenoceptors for noradrenaline couple to G proteins of the Gq/11 family and thereby increase the cytoplasmic levels of the second messengers inositol trisphosphate and diacylglycerol (Table 1). The dopamine Dr and D5-receptors and the (3-adrenoceptors for noradrenaline, finally, couple to Gs and thereby increase the cytoplasmic level of cyclic AMP. 

Sir Henry Dale noticed that the different esters of choline elicited responses in isolated organ preparations which were similar to those seen following the application of either of the natural substances muscarine (from poisonous toadstools) or nicotine. This led Dale to conclude that, in the appropriate organs, acetylcholine could act on either muscarinic or nicotinic receptors. Later it was found that the effects of muscarine and nicotine could be blocked by atropine and tubocurarine, respectively. Further studies showed that these receptors differed not only in their molecular structure but also in the ways in which they brought about their physiological responses once the receptor has been stimulated by an agonist. Thus nicotinic receptors were found to be linked directly to an ion channel and their activation always caused a rapid increase in cellular permeability to sodium and potassium ions. Conversely, the responses to muscarinic receptor stimulation were slower and involved the activation of a second messenger system which was linked to the receptor by G-proteins. 

Figure 2.8. Location of muscarinic receptors and their link to second messenger...

Acetylcholine acts at two different types of cholinergic receptors [see (1) and (2) in Fig. 2.5]. Muscarinic receptors bind ACh as well as other agonists (muscarine, pilocarpine, bethanechol) and antagonists (atropine, scopolamine). There are at least five different types of muscarinic receptors (M1-M5). All have slow response times. They are coupled to G proteins and a variety of second messenger systems. When activated, the final effect can be to open or close channels for K, Ca ", or CL (Bonner, 1989). Nicotinic receptors are less abundant than the muscarinic type in the CNS. They bind ACh as well as agonists such as nicotine or an-... 

As indicated in Chapter 6, muscarinic receptor subtypes have been characterized by binding studies and cloned. Several cellular events occur when muscarinic receptors are activated, one or more of which might serve as second messengers for muscarinic activation. All muscarinic receptors appear to be of the G protein-coupled type (see Chapter 2 and Table 7-1). Muscarinic agonist binding activates the inositol trisphosphate (IP3), diacylglycerol (DAG) cascade. Some evidence... 

In heart, muscarinic receptors inhibit adenylyl cyclase, via activation of PTX-sensitive G (35,80,81,136,137). However, K+ channel opening in response to muscarinic stimulation is not the result of decreased levels of cAMP [138,139], Evidence obtained using patch-clamped cells [160] argues against involvement of any second messenger at all [141-143] in regulation of the K+ channel. Moreover, experiments with inside-out patches demonstrate unequivocally that K+ channels couple directly to a receptor-regulated G protein [144,145], We call this functionally identified G protein Gk. 

Initial indications for direct receptor-G protein-K+ channel coupling came from experiments which examined atrial muscarinic receptor regulation of K+ channels present in a cell-attached patch [161]. It was found that K+ channels in the patch are insensitive to acetylcholine (ACh) added to the bath, i.e., to the cell membrane outside the physically and electrically isolated patch. However, application of acetylcholine directly to the patch, using a specially constructed pipette opened the K+ channels. If the effect of acetylcholine on the heart atrial K+ channels were mediated by a change in the intracellular concentration of a second messenger, such as Ca2+ or cAMP, application of acetylcholine outside of the patch should have elicited a response. Moreover, the coupling mechanism was not addressed by this experiment. 

McKinney M. 1993. Muscarinic receptor subtype-specific coupling to second messengers in neuronal systems. Prog Brain Res 98 333-340. 

Acetylcholine receptors (AChRs) are of two types muscarinic (mAChR) and nicotinic (nAChR) based on the agonist activities of the natural alkaloids, muscarine and nicotine, respectively. These receptors are functionally different. The muscarinic type being G-protein coupled receptors mediate a slow metabolic response via second messenger cascades, while the nicotinic type are ligand-gated ion channels, which mediate a fast synaptic transmission of the neurotransmitter. Skeletal muscles are enriched with nAChRs and are devoid of mAChRs. 

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