Transient Receptor Potential-Canonical (TRPC) channels are mammalian homologs of Transient Receptor Potential (TRP), a Ca(2+)-permeable channel involved in the phospholipase C-regulated photoreceptor activation mechanism in Drosophila. The seven mammalian TRPCs constitute a family of channels which have been proposed to function as store-operated as well as second messenger-operated channels in a variety of cell types. TRPC channels, together with other more distantly related channel families, make up the larger TRP channel superfamily. This review summarizes recent findings on the structure, regulation and function of the apparently ubiquitous TRPC cation channels.
Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a "closed-loop" form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.
The nature of Cl− conductance(s) participating in transepithelial anion secretion by renal inner medullary collecting duct (IMCD, mIMCD‐K2 cell line) was investigated.
Extracellular ATP (100 μM) stimulated a transient increase in both whole‐cell Cl− conductance and intracellular free Ca2+. In contrast, ionomycin (10–100 nM) caused a sustained increase in whole‐cell Cl− conductance. Pre‐loading cells with the Ca2+ buffer BAPTA abolished the ATP‐dependent responses and delayed the onset of the increase observed with ionomycin.
The Ca2+‐activated whole‐cell Cl− current stimulated by ATP (peak) and ionomycin (maximal) displayed (i) a linear steady‐state current‐voltage relationship and (ii) time and voltage dependence with slow activation at +80 mV and slow inactivation at −80 mV. In BAPTA‐loaded cells, ionomycin‐elicited whole‐cell currents exhibited pronounced outward rectification with time‐dependent activation/inactivation.
Ca2+‐activated and forskolin‐activated Cl− conductances co‐exist since ATP activation of whole‐cell current occurred during a maximal stimulation by forskolin in single cell recordings.
In IMCD epithelial layers, ATP and ionomycin stimulated an inward short circuit current (Isc) dependent upon basal medium Na+ and Cl−/HCO3− but independent of the presence of apical bathing medium Na+ and Cl−/HCO3−. This was identical to forskolin stimulation and consistent with transepithelial anion secretion.
PCR amplification of reverse‐transcribed mRNA using gene‐specific primers demonstrated expression of both cystic fibrosis transmembrane conductance regulator (CFTR) mRNA and Ca2+‐activated Cl− channel (mCLCA1) mRNA in mIMCD‐K2 cells.
Ca2+ and forskolin‐activated Cl− conductances participate in anion secretion by IMCD.
In a variety of cell types, activation of phospholipase C-linked receptors results in the generation of intracellular Ca2+ signals comprised of components of both intracellular Ca2+ release, and enhanced entry of Ca2+ across the plasma membrane. This entry of Ca2+ occurs by either of two general mechanisms: the release of stored Ca2+ can activate, by an unknown mechanism, store-operated channels in the plasma membrane, a process known as capacitative calcium entry. Alternatively, second messengers generated at the plasma membrane can activate Ca2+ channels more directly, a non-capacitative calcium entry process. This review summarizes current knowledge of the underlying signaling mechanisms and the nature of the channel molecules responsible for these two general categories of regulated Ca2+ entry.
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