Adenylate cyclase receptor linked

Activation of neostriatal tyrosine hydroxylase was observed when cyclic AMP was added to high speed supernatants from rat neostriatum (133). Intraventricular injection of dibutyryl cyclic AMP stimulated tyrosine hydroxylation in the neostriatum (134). However, it is still questionable if under physiological conditions this cyclic AMP involvement in the feedback control of tyrosine hydroxylase activity is mediated by presynaptic dopamine receptors or by presynaptic allo-receptors. In addition, if a dopamine sensitive adenylate cyclase is involved in the regulation of neostriatal tyrosine hydroxylase activity it is relevant to know if this adenylate cyclase is linked to a D-1 and/or a D-2 receptor. At this point in time experimental data are not in favour of the presence of a D-l receptor linked to an adeiylate cyclase on the varicosities of dopaminergic neurons in the neostriatum. E.g. concentrations of dopamine agonists stimulating cyclic AMP formation inhibit tyrosine... 

It is perhaps not surprising that DA produces such mixed effects. The Di receptor is primarily linked to the activation of adenylate cyclase and then protein kinase A. The response to its activation will therefore depend on the ion channels and other proteins modulated by the kinase which can vary from one neuron to another. Since the D2 receptor is not so closely associated with just one G-protein, this gives it the potential for even more effects (see Greenhoff and Johnson 1997). 

Histamine receptors were first divided into two subclasses Hi and H2 by Ash and Schild (1966) on the basis that the then known antihistamines did not inhibit histamine-induced gastric acid secretion. The justification for this subdivision was established some years later when Black (see Black et al. 1972) developed drugs, like cimetidine, that affected only the histamine stimulation of gastric acid secretion and had such a dramatic impact on the treatment of peptic ulcers. A recently developed H2 antagonist zolantidine is the first, however, to show significant brain penetration. A further H3 receptor has now been established. It is predominantly an autoreceptor on histamine nerves but is also found on the terminals of aminergic, cholinergic and peptide neurons. All three receptors are G-protein-coupled but little is known of the intracellular pathway linked to the H3 receptor and unlike Hi and H2 receptors it still remains to be cloned. Activation of Hi receptors stimulates IP3 formation while the H2 receptor is linked to activation of adenylate cyclase. 

Initially, it was proposed that the 5-HTjb receptor is located exclusively in the brain of the rat and some other rodents, whereas the 5-HTid receptor, a close species homolog, is specific to the guinea pig and higher mammalian species, including humans (Waeber et al., 1989). However, recent studies have characterized the 5-HTiB receptor also in the human brain (Bidmon et al., 2001 Varnas et al., 2005). The 5-HT, B receptor is linked to the inhibition of adenylate cyclase, and is located at presynaptic (5-HT axon terminals) and postsynaptic... 

Other oncogenes code for proteins that bind guanine nucleotides, and others code for nuclear proteins. The guanine nucleotide-binding proteins, the so-called G proteins, affect several key reactions. Some G proteins are stimulatory, whereas others are inhibitory. For example, they link hormone receptors to adenylate cyclase, they translocate... 

Two major second messenger systems have been evolved. When the a-sub-unit is temporarily linked to adenylate cyclase, the enzyme is activated and catalyzes the transformation of ATP to cAMP. This second messenger activates a specific protein kinase, which in turn phosphorylates target proteins in the cell leading to the overall physiological response. Such a pathway is utilized by the /1-adrenoceptor, dopaminergic, and prostaglandin receptors, etc. 

All of these experimental approaches have been adopted in neutrophil studies to show that activation of several receptor-mediated functions occurs via the participation of heterotrimeric G-proteins. In many cases, the conventional Gai/Gas nomenclature is used to describe these G-proteins, even though the subunits may not be linked to either inhibition or activation of adenylate cyclase. The nomenclature used is based on structural and functional similarities to other Ga-subunits in other cell types, and also on their sensitivities to cholera and pertussis toxins. Several of these G-proteins... 

Many monoamine neurotransmitters are now thought to work by this receptor-linked second messenger system. In some cases, however, stimulation of the posts)maptic receptors can cause the inhibition of adenylate cyclase activity. For example, D2 dopamine receptors inhibit, while receptors stimulate, the activity of the cyclase. 

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. 

Two types of dopamine receptors have been characterized in the mammalian brain, termed and D2. This subtyping largely arose in response to the finding that while all types of clinically useful neuroleptics inhibit dopaminergic transmission in the brain, there is a poor correlation between reduction in adenylate cyclase activity, believed to be the second messenger linked to dopamine receptors, and the clinical potency of the drugs. This was particularly true for the butyrophenone series (e.g. haloperidol) which are known to be potent neuroleptics and yet are relatively poor at inhibiting adenylate cyclase. 

Detailed studies of the binding of H-labelled haloperidol to neuronal membranes showed that there was a much better correlation between the therapeutic potency of a neuroleptic and its ability to displace this ligand from the nerve membrane. This led to the discovery of two types of dopamine receptor that are both linked to adenylate cyclase but whereas the Di receptor is positively linked to the cyclase, the D2 receptor is negatively linked. It was also shown that the receptor is approximately 15 times more sensitive to the action of dopamine than the D2 receptor conversely, the receptor has a low affinity for the butyrophenone and atypical neuroleptics such as clozapine, whereas the D2 receptor appears to have a high affinity for most therapeutically active neuroleptics. 

Dopamine has been implicated in a number of psychiatric conditions of which schizophrenia and the affective disorders are the most widely established. Five major subtypes of dopamine receptors have now been cloned. These are divided into two main groups, and D2 respectively. The receptors consist of Di and D5 types and are positively linked to the adenylate cyclase second messenger system, while the D2 group consists of the D2, D3 and D4 receptors which are negatively linked to the adenylate cyclase system. 

Since they are linked to G-proteins, opioid receptors affect intracellular Ca and protein phosphorylation. Another principal biochemical effect of opiates is the inhibition of adenylate cyclase (AC), which decreases cAMP production. 

The picture that has emerged from these studies is of an initial interaction of a stimulus with a matched portion of a receptor protein embedded in the cell membrane (13,65). This initial interaction causes stimulation of the linked G-protein to form cGMP. This is coupled to the reactivity of adenylate cyclase in the cells, leading to increased levels of cAMP, which opens ion channels in the cell membrane. A similar sequence can alternatively activate inositol phosphate as a second messenger. Either odorants, cAMP or cGMP can cause a potential change in the membrane (13,70,71,72). As in hormone-sensitive and neurotransmitter-... 

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