Cyclic nucleotide receptors

In cyclic nucleotide-regulated channels, this domain serves as a high-affinity binding site for 3-5 cyclic monophosphates. The CNBD of channels has a significant sequence similarity to the CNBD of most other classes of eukaryotic cyclic nucleotide receptors and to the CNBD of the prokaryotic catabolite activator protein (CAP). The primary sequence of CNBDs consists of approximately 120 amino acid residues forming three a-helices (oA-aC) and eight (3-strands ( 31- 38). 

The intracellular processes which precede membrane activation appear to differ from those of MOE neurones, in that cyclic nucleotide gating may not occur. The transduction process which induces current flow in snake VN neurones, utilises as a putative second-messenger the modulator compound inositol triphosphate — Ins. (1,4,5) P3 = IP3 (Liu et al, 1999 Taniguichi et al, 2000). The proposed channel component associated with the microvillous membrane is one of the transient receptor potential family (TRPC-2 Heading Fig., pp. 94), the p-splice... 

Second messengers relay the primary signal. The distinction between second messengers and normal transducers is that second messengers are small molecules. Extracellular signals of various kinds can activate intracellular pathways that cause an increase in the concentration of a small molecule messenger. All of these pathways involve G-protein coupled receptors. There are two second messengers that you need to know about cyclic nucleotides and calcium. 

Cyclic nucleotides are made in response to receptor activation. The receptor activates a G-protein that, in turn, activates adenylyl cyclase to make the cyclic nucleotide. To complete the signaling, the increase in cAMP concentration activates a specific protein kinase (serine/threo-nine), cAMP-dependent protein kinase (A kinase) (Fig. 9-7). To turn off the signaling pathway, the cyclic nucleotides are destroyed by enzymes called phosphodiesterases. These cleave cAMP to AMP. 

Membrane depolarization typically results from an increase in Na+ conductance. In addition, mobilization of intracellular Ca2+ from the endoplasmic or sarcoplasmic reticulum and the influx of extracellular Ca2+ appear to be elicited by ACh acting on muscarinic receptors (see Ch. 22). The resulting increase in intracellular free Ca2+ is involved in activation of contractile, metabolic and secretory events. Stimulation of muscarinic receptors has been linked to changes in cyclic nucleotide concentrations. Reductions in cAMP concentrations and increases in cGMP concentrations are typical responses (see Ch. 21). These cyclic nucleotides may facilitate contraction or relaxation, depending on the particular tissue. Inhibitory responses also are associated with membrane hyperpolarization, and this is a consequence of an increased K+ conductance. Increases in K+ conductance may be mediated by a direct receptor linkage to a K+ channel or by increases in intracellular Ca2+, which in turn activate K+ channels. Mechanisms by which muscarinic receptors couple to multiple cellular responses are considered later. 

Hatton, G. I. and Yang, Q. Z. Synaptically released histamine increases dye coupling among vasopressinergic neurons of the supraoptic nucleus mediation by H[ receptors and cyclic nucleotides. /. Neurosci. 16 123-129,1996. 

Nakamura, T. and Gold, G. H. A cyclic nucleotide-gated conductance in olfactory receptor cilia. Nature 325 442-444,1987. 

Chen, T. Y. and Yau, K. W. Direct modulation by Ca2+-calmodulin of cyclic nucleotide-activated channel of rat olfactory receptor neurons. Nature 368 545-548,1994. 

Spehr, M. et al. 3-phosphoinositides modulate cyclic nucleotide signaling in olfactory receptor neurons. Neuron 33 731-739, 2002. 

Recently, it was shown that the thromboxane receptor itself is a substrate ofcGMP-PK and cAMP-PK in HEK293 cells, HEL cells, or with purified enzymes in vitro. Phosphorylation of its cytoplasmic carboxyterminal domain prevented the thromboxane receptor from coupling to and activating G-proteins [36, 37]. For intact platelets, TxA2 receptor phosphorylation has not yet been shown, however, it would provide another explanation for the inhibition of PLC activation and subsequent intracellular Ca2+ elevation and granule secretion in response to cyclic nucleotides. 

Gorshkova, I., J.L. Moore, K.H. McKenney, and F.P. Schwarz. 1995. Thermodynamics of cyclic nucleotide binding to the cAMP receptor protein and its T127L mutant. J Biol Chem 270 21679-21683. 

Perception of bitter taste can take place via G-proteins the a-subrmit of these G-proteins is know as gustducin and is highly homologous with transducin. The corresponding receptors are just beginning to be characterized (Hohn, 1999). A phosphodiesterase with specificity for cyclic nucleotides and a cyclic nucleotide-gated ion charmel... 

---