Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma

Airway hyperresponsiveness and inflammation are fundamental hallmarks of allergic asthma that are accompanied by increases in certain polycations, such as eosinophil cationic protein. Levels of these cations in body fluids correlate with asthma severity. We show that polycations and elevated extracellular calcium activate the human recombinant and native calcium-sensing receptor (CaSR), leading to intracellular calcium mobilization, cyclic adenosine monophosphate breakdown, and p38 mitogen-activated protein kinase phosphorylation in airway smooth muscle (ASM) cells. These effects can be prevented by CaSR antagonists, termed calcilytics. Moreover, asthmatic patients and allergen-sensitized mice expressed more CaSR in ASMs than did their healthy counterparts. Indeed, polycations induced hyperreactivity in mouse bronchi, and this effect was prevented by calcilytics and absent in mice with CaSR ablation from ASM. Calcilytics also reduced airway hyperresponsiveness and inflammation in allergen-sensitized mice in vivo. These data show that a functional CaSR is up-regulated in asthmatic ASM and targeted by locally produced polycations to induce hyperresponsiveness and inflammation. Thus, calcilytics may represent effective asthma therapeutics

Amino acid transport systems of lysosomes: Possible substitute utility of a surviving transport system for one congenitally defective or absent

Ways in which other transport systems may compensate for one that is genetically defective are considered. Comparisons of the transport systems of organelles (here the lysosome) with the transport system at the plasma membrane has significant implications for chemotherapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44194/1/10540_2005_Article_BF01116456.pd

Diabetes enhances activity of alanine transport in liver plasma membrane vesicles

In the present study plasma membrane vesicles were prepared from livers of control and alloxan-induced diabetic rats and the substrate specificity and kinetic characteristics of alanine transport determined in both groups. Sodium-dependent alanine uptake at physiological alanine concentrations (100 microM) was enhanced threefold in diabetic as compared with control animals (0.31 +/- 0.04 vs. 0.11 +/- 0.01 nmol X mg protein-1 X 10 s-1). This accelerated influx corresponded to a three- to fourfold increase in the Vmax of alanine transport in diabetic versus control group (7.1 +/- 2.1 vs. 1.6 +/- 0.2 nmol X mg protein-1 X 10 s-1, P less than 0.05), whereas the Km of alanine uptake was unchanged (2.8 +/- 1.2 vs. 1.4 +/- 0.1 mM). Other neutral amino acids (20 mM) inhibited alanine transport to a similar degree in both groups. The sodium-dependent influx of glutamine (100 microM) was similar in diabetic and control groups (0.17 +/- 0.03 and 0.14 +/- 0.02 nmol X mg protein-1 X 10 s-1, respectively). The initial velocity of 22Na uptake (80 mM) into vesicles and half-maximal stimulation of alanine transport was achieved at essentially identical sodium concentrations (approximately 40 mM) in both groups