Messenger (Los Angeles, Calif. : Print)最新文献

Calcium release into the cytosol via the inositol 1,4,5-trisphosphate receptor (IP₃R) calcium channel is important for a variety of cellular processes. As a result, impairment or inhibition of this release can result in disease. Recently, mutations in all four domains of the IP₃R have been suggested to cause diseases such as ataxia, cancer, and anhidrosis; however, most of these mutations have not been functionally characterized. In this review we summarize the reported mutations, as well as the associated symptoms. Additionally, we use clues from transgenic animals, receptor stoichiometry, and domain location of mutations to speculate on the effects of individual mutations on receptor structure and function and the overall mechanism of disease.

Mammalian cells express three highly conserved inositol 1,4,5-trisphosphate (IP₃) receptor types (IP₃R1, IP₃R2 and IP₃R3), which have broadly similar characteristics, but markedly different distributions, and form homo- or heterotetrameric Ca²⁺ channels in endoplasmic reticulum (ER) membranes. A vast array of published work details how mature, ER membrane-located IP₃ receptor tetramers are regulated, but much less attention has been paid to the intriguing questions of how the tetramers are assembled and destroyed as part of their natural life cycle. Are they assembled at the ER membrane from nascent, or completely translated polypeptides? How are they disassembled and degraded? These questions and other recently defined modes of IP₃ receptor processing will be briefly reviewed.

Lysosomes are key acidic Ca²⁺ stores. The principle Ca²⁺-permeable channels of the lysosome are TRP mucolipins (TRPMLs) and NAADP-regulated two-pore channels (TPCs). Recent studies, reviewed in this collection, have linked numerous neurodegenerative diseases to both gain and loss of function of TRPMLs/TPCs, as well as to defects in acidic Ca²⁺ store content. These diseases span rare lysosomal storage disorders such as Mucolipidosis Type IV and Niemann-Pick disease, type C, through to more common ones such as Alzheimer and Parkinson disease. Cellular phenotypes, underpinned by endo-lysosomal trafficking defects, are reversed by chemical or molecular targeting of TRPMLs and TPCs. Lysosomal Ca²⁺ channels therefore emerge as potential druggable targets in combatting neurodegeneration.

Lysosomes are the central organelles responsible for macromolecule recycling in the cell. Lysosomal dysfunction is the primary cause of lysosomal storage diseases (LSDs), and contributes significantly to the pathogenesis of common neurodegenerative diseases. The lysosomes are also intracellular stores for calcium ions, one of the most common second messenger in the cell. Lysosomal Ca²⁺ is required for diverse cellular processes including signal transduction, vesicular trafficking, autophagy, nutrient sensing, exocytosis, and membrane repair. In this review, we first summarize some recent progresses in the studies of lysosome Ca²⁺ regulation, with a focus on the newly discovered lysosomal Ca²⁺ channels and the mechanisms of lysosomal Ca²⁺ store refilling. We then discuss how defects in lysosomal Ca²⁺ release and store maintenance cause lysosomal dysfunction and neurodegeneration.

ADP-ribosyl cyclases are multifunctional enzymes involved in the metabolism of nucleotide derivatives necessary for Ca²⁺ signalling such as cADPR and NAADP. Although Ca²⁺ signalling is a critical regulator of early development, little is known of the role of ADP-ribosyl cyclases during embryogenesis. Here we analyze the expression, activity and function of ADP-ribosyl cyclases in the embryo of the sea urchin - a key organism for study of both Ca²⁺ signalling and embryonic development. ADP-ribosyl cyclase isoforms (SpARC1-4) showed unique changes in expression during early development. These changes were associated with an increase in the ratio of cADPR:NAADP production. Over-expression of SpARC4 (a preferential cyclase) disrupted gastrulation. Our data highlight the importance of ADP-ribosyl cyclases during embryogenesis.

Two-pore channels are endolysosomal Ca²⁺ release channels involved in proper trafficking to and from those organelles. They are the likely targets for the Ca²⁺-mobilizing messenger NAADP, and are further regulated by a variety of mechanisms including phosphoinositide levels and Rab proteins. As discussed here, recent studies highlight a role for these channels in the pathomechanism(s) underlying Parkinson's disease, with important implications for possible alternative treatment strategies.

Spontaneous Ca²⁺ waves, also termed store-overload-induced Ca²⁺ release (SOICR), in cardiac cells can trigger ventricular arrhythmias especially in failing hearts. SOICR occurs when RyRs are activated by an increase in sarcoplasmic reticulum (SR) luminal Ca²⁺. Carvedilol is one of the most effective drugs for preventing arrhythmias in patients with heart failure. Furthermore, carvedilol analogues with minimal β-blocking activity also block SOICR showing that SOICR-inhibiting activity is distinct from that for β-block. We show here that carvedilol is a potent inhibitor of cADPR-induced Ca²⁺ release in sea urchin egg homogenate. In addition, the carvedilol analog VK-II-86 with minimal β-blocking activity also suppresses cADPR-induced Ca²⁺ release. Carvedilol appeared to be a non-competitive antagonist of cADPR and could also suppress Ca²⁺ release by caffeine. These results are consistent with cADPR releasing Ca²⁺ in sea urchin eggs by sensitizing RyRs to Ca²⁺ involving a luminal Ca²⁺ activation mechanism. In addition to action on the RyR, we also observed inhibition of inositol 1,4,5-trisphosphate (IP₃)-induced Ca²⁺ release by carvedilol suggesting a common mechanism between these evolutionarily related and conserved Ca²⁺ release channels.