Calcium intracellular receptors

Neutrophils represent an ideal system for studying osmotic effects on exocytosis. Stimulation of cytochalasin-B-treated neutrophils with the chemotactic peptide Jlf-formylmethionyl-leucyl-phenyl-alanine (FMLP) results in a rapid compound exocytosis up to 80% of lysosomal enzymes are released within 30 s (9-14). Secretion appears to be triggered by a rise in the level of cytosolic free calcium (15-18) promoted in part by entry of extracellular calcium through receptor-gated channels and in part by release of calcium that is sequestered or bound at some intracellular site (19-21). In this presentation, we augment our previously published data (22,23), which demonstrates that lysosomal enzyme release from neutrophils is inhibited under hyperosmotic conditions and that the rise in cytosolic calcium preceding secretion is inhibited as well. 

Once formed, 1,25-DHCC acts on duodenal epithelial cells as a lipid-soluble hormone. Its intracellular receptor (a Zn-finger protein) binds to response elements in enhancer regions of DNA to induce the synthesis of calcium-binding proteins thought to play a role in stimulating calcium uptake from the GI tract. 

Fig. 7.1 Localization of some mutations and polymorphisms reported for the calcium-sensing receptor (CASK). The relationship between the CASK gene exons (II to Vll) and the modular domains of the 1078-amino acid protein are indicated. The 610-amino acid exctracellular domain (BCD) is encoded by exons II to VI. The beginning of exon VII encodes the BCD. The remainder of exon VII encodes the transmembrane domain (TMD) of approx. 250 amino acids that includes the membrane-spanning helices TM1-TM7 (indicated by the hatched boxes), the extracellular and intracellular...

The D vitamins are a group of sterols that have a hormone-like funciion. The active molecule, 1,25-dihydroxycholecalciferol (1,25 diOH D3), binds to intracellular receptor proteins. The 1,25-diOH D3-receptor complex interacts with DNA in the nucleus of target cells in a manner simiar to that of vitamin A (see Figure 28.20), and either selectively stimulates gene expression, or specifically represses gene transcription. The most prominent actions of 1,25-diOH D3 are to regulate the plasma levels of calcium and phosphorus. 

Meanwhile, the polar IP3 moiety binds to intracellular receptors on the endoplasmic reticulum, resulting in the liberation of calcium into the cytosol. The calcium binds to calmodulin, which then activates another group of protein kinases (the Ca2+/CaM-dependent protein kinases). Hormonal stimulation can be short-lived because IP3 and DG are rapidly degraded to inactive forms that are ultimately recycled to PIP2 Ca2+ is pumped back into the endoplasmic reticulum, where it is sequestered. 

Fig. 9. The interaction of ACTH with the cyclic AMP and calcium intracellular messenger systems in the regulation of steroidogenesis in the adrenocortical zona glomerulosa cell comparison with angiotensin II and potassium. ACTH activates both adenylate cyclase and calcium influx, here shown as involving two receptor subtypes (R, and R2) although such receptor subtypes have not been identified. The A-kinase and calmodulin systems produce individual responses of characteristic amplitudes and time-courses, which combine to give the observed response of the intact cell. The sequence of events for ACTH is compared to those for the other two major stimuli of steroidogenesis in the zona glomerulosa cell, angiotensin II and potassium. From Ref. 41.

RX 783006 DAMGO. ryanodine is an alkaloid from Ryania speciosa (Flacourtiaceae). It has been used as an INSECTICIDE, but is now superseded. It is a calcium-transport blocker, binding to intracellular receptor channels in the endoplasmic reticulum. It is used as a pharmacological tool. 

PTH also acts to increase absorption of calcium ion by the small intestine. It does this indirectly by promoting the formation of active vitamin D in the kidney. PTH acts on the final, rate-limiting step in vitamin D synthesis, the formation of 1,25-dihydroxycholecalciferol in the kidney. If PTH is low, formation of the inactive derivative, 24,25-dihydroxycholecalciferol, is stimulated instead. Vitamin D acts on intracellular receptors in the small intestine to increase transcription of genes encoding calcium uptake systems, to up-regulate their expression. 

Calcium ion is widely recognized as a major regulator of intracellular metabolism in eukaryotes. The cation is frequently involved as a coupling factor linking diverse humoral stimuli to resultant cellular responses. Calmodulin appears to function as a major, if not the predominant, intracellular receptor for Ca +, coupling changes in intracellular free Ca + concentrations to subsequent cellular responses. 

In summary, one might expect to find calcium-binding proteins playing six distinct roles in living systems 1. binding sites on the outer surface of plasma membranes, 2. transport carriers in cell membranes, 3. intracellular storage reservoirs of calcium, 4. intracellular receptors linked to calcium function (i.e., in contractile systems), 5. as part of matrix of mineralized tissues and, 6. as a co-factor in calcium-activated enzymes. 

Before the discovery of specific LP receptors, there were multiple hypotheses proposed to explain the physiological signaling response mechanisms provoked by LPs. For instance, it was thought that LPs could act as calcium chelators, ionophores, membrane disrupters, second messengers, or act via intracellular receptors (reviewed in (Chun, 1999 Fukushima et al., 2001). Heterologous expression of cloned receptors was performed to prove that extracellular receptors mediated the FP signaling pathway. Two cell lines, RH7777 (hepatoma)... 

Agents that increase intracellular calcium, causing an influx of extracellular calcium following receptor activation or the release of calcium from intracellular stores, cause endothelium- (and NO-) dependent relaxation in... 

With the onset of ischemia, there is an influx of sodium, calcium and chloride with the concomitant release of potassium. The movement of the sodium and chloride results in the influx of water and brain swelling (Kimelberg, 2005). The influx of calcium is compounded secondarily by the release of endogenous calcium stores from the endoplasmic reticulum (Phillis et al, 2002). The excessive rise in Ca that results from an ischemia-induced failure of these homeostatic mechanisms represents a non-physiological stimulus that activates a wide array of intracellular receptors, membrane channels, proteins and enzymes, which lead to the compromise of the cell s functional and structural integrity. 

Yates, A. J., VanBrocklyn, J., Saqr, H. E., Guan, Z., Stokes, B. T., and O Dorisio, M. S., 1993, Mechanisms through which gangliosides inhibit PDGF-stimulated mitogenesis in intact Swiss 3T3 cells Receptor tyrosine phosphorylation, intracellular calcium, and receptor binding, Exp. Cell Res. 204 38-45. 

Another mechanism in initiating the contraction is agonist-induced contraction. It results from the hydrolysis of membrane phosphatidylinositol and the formation of inositol triphosphate (IP3)- IP3 in turn triggers the release of intracellular calcium from the sarcoplasmic reticulum and the influx of more extracellular calcium. The third mechanism in triggering the smooth muscle contraction is the increase of calcium influx through the receptor-operated channels. The increased cytosolic calcium enhances the binding to the protein, calmodulin [73298-54-1]. 

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

---