G proteins, second messenger systems

Cellular processes involving the classic ligand-receptor interaction and beyond (e.g., G-proteins, second messenger systems)... 

Baclofen (Figure 89.12) is a presynaptic and postsyn-aptic GABA-B receptor agonist. When activated, a G protein second-messenger system stimulates opening of K channels, thereby hyperpolarizing the neuron [23,24). 

G-protein receptor systems are widespread in living systems. They are found in many animals and microbes. Both vision and smell in humans depend on G-proteins (Campbell et al., 1999), and glucagon receptors use the system to produce a second messenger called cyclic AMP (cAMP). Receptors for epinephrine, angiotensin, endorphins, and acetylcholine also use this G-protein second messenger mechanism (Sleight and Lieberman, 1995). 

Furthermore, each class has at least two subtypes of receptors alr a2, Plr and P2- All of these receptors are linked to G proteins and second messenger systems that carry out the intracellular effects. 

G protein Receptor subtype Second messenger system... 

It is obvious that Li+ has several inhibitory effects on the adenylate cyclase-dependent second-messenger system. Many of these influences can be counteracted by the addition of Mg2+, therefore it is probable that Li+ is competing for Mg2+ binding sites on, and thereby interfering with the activity of, the catalytic enzyme itself and/or of the associated G proteins. 

PTHrP). The receptor signal is mediated by G proteins that activate adenylyl cyclase and the phosphatidylinositol-calcinm second-messenger system. Mntations of PTHRl are associated with abnormalities of development related to altered PTHrP ligand binding. PTHrP is a key paracrine peptide responsible for osteochondrogenesis dnring fetal development (55,56). 

An excitatory neurotransmitter such as noradrenaline or serotonin acts on its receptor and activates the intermembrane G-protein by converting GDP to GTP thereby linking the receptor to the second messenger system, usually adenylate cyclase. 

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. 

Some sensory neurons of the VNO express two gene superfamilies, termed Vlr and V2r, that encode over 240 proteins of the seven-transmembrane type (Matsunami and Buck, 1997). These G-protein-linked putative pheromone receptors are distantly related to the main olfactory system s receptors. Receptors of the VNO are linked to different G-proteins, and their extracellular N-terminal domains are longer than those of the receptors in the main olfactory system. (Vi receptors are linked to Gi-proteins and V2 receptors to Go-proteins). The intracellular excitation mechanism in VNO sensory neurons also differs from that in the main olfactory systems instead of linking to adenylyl cyclase, the VNO receptors activate the phosphoinositol second messenger system. This has been demonstrated in several mammalian species. In hamsters, aphrodisin increases inositol 1,4,5-trisphosphate (IP3) levels in VNO membranes. Boar seminal fluid and urine stimulate increases of IP3 in the VNO of the female pig. (However, in the pig, the VNO is not necessarily essential for responses to pheromones [Dorries etal., 1997]). 

One of the best-characterized effectors and second messenger systems is the cAMP cascade that can be either activated or inhibited by neurotransmit-ter/neuropeptide receptors, including those implicated in anxiety/stress such as CRE Receptors that activate cAMP synthesis couple with the stimulatory G protein, Gsa, and those that inhibit this second messenger couple with the inhibitory G protein, Gia, and these either stimulate or inhibit adenylyl cyclase, the effector enzyme responsible for synthesis of cAMP (Duman and Nestler 1999). There are at least nine different forms of adenylyl cyclase that have been identified by molecular cloning, each with a unique distribution in the brain. The different types of adenylyl cyclase are activated by Gsa as well as the diterpene forskolin, but are differentially regulated by Gia, the Py subunits, Ca, and by phosphorylation. This provides for fine control of adenylyl cyclase enzyme activity and regulation by other effector pathways. 

The metabotropic glutamate receptor family includes at least seven different types of G protein-coupled receptors (mGluRj 7). These are linked to different second messenger systems and lead to the increase of intracellular Ca or the decrease of cyclic AMP (cAMP). The increase of intracellular Ca leads to the phosphorylation of target proteins in the cell. 

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-... 

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