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The orphan nuclear receptor ERRα is the most extensively researched member of the estrogen-related receptor family and holds a pivotal role in various functions associated with energy metabolism, especially in tissues characterized by high energy requirements, such as the heart, skeletal muscle, adipose tissue, kidney, and brain. Abscisic acid (ABA), traditionally acknowledged as a plant stress hormone, is detected and actively functions in organisms beyond the land plant kingdom, encompassing cyanobacteria, fungi, algae, protozoan parasites, lower Metazoa, and mammals. Its ancient, cross-kingdom role enables ABA and its signaling pathway to regulate cell responses to environmental stimuli in various organisms, such as marine sponges, higher plants, and humans. Recent advancements in understanding the physiological function of ABA and its mammalian receptors in governing energy metabolism and mitochondrial function in myocytes, adipocytes, and neuronal cells suggest potential therapeutic applications for ABA in pre-diabetes, diabetes, and cardio-/neuroprotection. The ABA/LANCL1-2 hormone/receptor system emerges as a novel regulator of ERRα expression levels and transcriptional activity, mediated through the AMPK/SIRT1/PGC-1α axis. There exists a reciprocal feed-forward transcriptional relationship between the LANCL proteins and transcriptional coactivators ERRα/PGC-1α, which may be leveraged using natural or synthetic LANCL agonists to enhance mitochondrial function across various clinical contexts. [ABSTRACT FROM AUTHOR]

ADP-ribosyl cyclases are ubiquitous enzymes responsible for synthesis from NA[D.sup.+] of the intracellular calcium-releasing signal molecules cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAAD[P.sup.+]). Here, we show that cyclases from lower and higher Metazoa also synthesize three adenylic dinucleotides from cADPR and adenine: diadenosine diphosphate and two isomers thereof. These dinucleotides are present and metabolized in mammalian cells and affect intracellular calcium and cell proliferation. The diadenosine diphosphate isomers are naturally occurring nucleotides containing an N-glycosidic bond different from the usual C1'-N9. The identification of these members of the family of NA[D.sup.+]-derived, calcium-active nucleotides opens new areas of investigation into their functional cooperation with cADPR and NAAD[P.sup.+] and into their involvement in the physiology and pathology of calcium-controlled cell functions. adenylic dinudeotides | NAD | cyclic ADP-ribose | cytotoxicity

Extracellular cyclic ADP-ribose potentiates ACh-induced contraction in bovine tracheal smooth muscle. Am J Physiol Lung Cell Mol Physiol 280: L98-L106, 2001.--Cyclic ADP-ribose (cADPR), a universal calcium releaser, is generated from [NAD.sup.+] by an ADP-ribosyl cyclase and is degraded to ADP-ribose by a cADPR hydrolase. In mammals, both activities are expressed as ectoenzymes by the transmembrane glycoprotein CD38. CD38 was identified in both epithelial cells and smooth myocytes isolated from bovine trachea. Intact tracheal smooth myocytes (TSMs) responded to extracellular cADPR (100 [micro]M) with an increase in intracellular calcium concentration ([[[Ca.sup.2+]].sub.i]) both at baseline and after acetylcholine (ACh) stimulation. The nonhydrolyzable analog 3-deaza-cADPR (10 nM) elicited the same effects as cADPR, whereas the cADPR antagonist 8-[NH.sub.2]-cADPR (10 [micro]M) inhibited both basal and ACh-stimulated [[[Ca.sup.2+]].sub.i] levels. Extracellular cADPR or 3-deaza-cADPR caused a significant increase of ACh-induced contraction in tracheal smooth muscle strips, whereas 8-[NH.sub.2]-cADPR decreased it. Tracheal mucosa strips, by releasing [NAD.sup.+], enhanced [[[Ca.sup.2+]].sub.i] in isolated TSMs, and this increase was abrogated by either [NAD.sup.+]-ase or 8-[NH.sub.2]-cADPR. These data suggest the existence of a paracrine mechanism whereby mucosa-released extracellular [NAD.sup.+] plays a hormonelike function and cADPR behaves as second messenger regulating calcium-related contractility in TSMs. acetylcholine; CD38; nicotinamide adenine dinucleotide/ cyclic adenosine 5'-diphosphate-ribose-mediated paracine mechanisms; calcium-related contraction of tracheal strips; adenosine 5'-diphosphate-ribosyl cyclase; cyclic adenosine 5'-diphosphate-ribose hydrolase.