CALP3

Role of acidic stores in secretory epithelia.[Pubmed:24832105]

Cell Calcium. 2014 Jun;55(6):346-54.

There is growing evidence that intracellular calcium plays a primary role in the pathophysiology of the pancreas in addition to its crucial importance in major physiological functions. Pancreatic acinar cells have a remarkably large amount of Ca(2+) stored in both the endoplasmic reticulum (ER) and the acidic stores. The vast majority of the classical ER Ca(2+) store is located in the basal part of the acinar cells with extensions protruding into the apical area, however, the acidic stores are exclusively located in the secretory granular area of the cells. Both types of Ca(2+) store respond to all three intracellular Ca(2+) messengers - inositol trisphosphate (InsP3), cyclic-ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). The two stores interact with each other via calcium-induced calcium release; however, they can be separated using pharmacological tools. The ER relies on sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) that can be blocked by the specific inhibitor thapsigargin. The acidic store requires a low pH that can be modified by blocking vacuolar H(+)-ATPase. The acidic store is particularly important for pathological processes in the pancreas. Acute pancreatitis is initiated as a result of calcium overload in the apical pole, which leads to trypsinogen activation; two major causes are gall bladder stones and excessive alcohol consumption. Excessive Ca(2+) release from the acidic stores plays a major role in both scenarios; however NAADP-induced calcium release from acidic stores is particularly important for bile-induced pancreatitis. Cell-permeable calmodulin (CaM) activators such as CALP3 boost the natural protective effect of CaM by inhibiting excessive calcium release from the internal stores through inositol trisphosphate (InsP3R) and ryanodine receptors (RyR). Alternatively calcium overload can be dramatically reduced by inhibiting Ca(2+)-release-activated Ca(2+) (CRAC) currents that are required to reload the internal stores and therefore provide effective protection against the major triggers of acute pancreatitis.

Ca2+ sensors modulate asthmatic symptoms in an allergic model for asthma.[Pubmed:12969760]

Eur J Pharmacol. 2003 Aug 22;476(1-2):151-7.

We previously described two novel peptides, Ca2+-like peptide (CALP) 1 and CALP2, which interact with Ca2+-binding EF hand motifs, and therefore have the characteristics to define the role of the Ca2+-sensing regulatory protein calmodulin in asthma. In the present study, the effects of the calcium-like peptides were investigated in an animal model for allergic asthma. For that purpose, sensitized guinea pigs were intratracheally pretreated with CALP1 or CALP2. Thirty minutes later, the animals were challenged with aerosolized ovalbumin. Acute bronchoconstriction was measured as well as characteristic features of asthma 6 and 24 hours (h) after challenge. Neither CALP1 nor CALP2 prevented the anaphylactic response elicited by ovalbumin challenge. However, CALP1 pretreatment attenuated the influx of inflammatory cells in the lungs 6 h after challenge. Furthermore, radical production by these cells was diminished both 6 and 24 h after challenge. Moreover, CALP1 completely inhibited airway hyperresponsiveness in vitro 24 h after challenge. We conclude that CALP1, as a selective calmodulin agonist, inhibits the development of asthmatic features probably via the attenuation of mast cell degranulation and radical production. Specific modulation of calmodulin activity might therefore be a potential new target for the treatment of allergic asthma.

A new type of Ca(2+) channel blocker that targets Ca(2+) sensors and prevents Ca(2+)-mediated apoptosis.[Pubmed:10877822]

FASEB J. 2000 Jul;14(10):1297-306.

Calmodulin (CaM), as well as other Ca(2+) binding motifs (i.e., EF hands), have been demonstrated to be Ca(2+) sensors for several ion channel types, usually resulting in an inactivation in a negative feedback manner. This provides a novel target for the regulation of such channels. We have designed peptides that interact with EF hands of CaM in a specific and productive manner. Here we have examined whether these peptides block certain Ca(2+)-permeant channels and inhibit biological activity that is dependent on the influx of Ca(2+). We found that these peptides are able to enter the cell and directly, as well as indirectly (through CaM), block the activity of glutamate receptor channels in cultured neocortical neurons and a nonselective cation channel in Jurkat T cells that is activated by HIV-1 gp120. As a consequence, apoptosis mediated by an influx of Ca(2+) through these channels was also dose-dependently inhibited by these novel peptides. Thus, this new type of Ca(2+) channel blocker may have utility in controlling apoptosis due to HIV infection or neuronal loss due to ischemia.

CALP3, a Ca2+-like peptide, is a potent Ca2+ channel blocker that activates EF hand motifs of Ca2+-binding proteins. CALP3 can functionally mimic increased [Ca2+]i by modulating the activity of Calmodulin (CaM), Ca2+ channels and pumps. CALP3 has the potential in controlling apoptosis in diseases such as AIDS or neuronal loss due to ischemia.

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