Our data show for the first time that UII-induced VSMCs proliferation and CREB activation requires a complex signalling pathway that involves on the one hand SOCE mediated by STIM1, Orai1, and TRPC1, and on the other hand EGFR, ERK, and CaMK activation.

Key points• The carotid body (CB) is a key chemoreceptor organ that mediates the hyperventilatory response to hypoxia, and contributes to the process of acclimatisation to chronic hypoxaemia.• Knowledge of CB physiology at the cellular and molecular levels has advanced considerably in recent times thanks to studies on lower mammals; however, information on humans is practically absent. Here we describe the properties of human CB cells in slice preparations or after enzymatic dispersion.• Besides glomus (type I) and glia-like, sustentacular (type II) cells, adult human CBs contain nestin-positive neural progenitor cells. The human CB also expresses high levels of glial cell line-derived neurotrophic factor. These properties are maintained at an advanced age.• Human glomus cells contain a relatively high density of voltage-dependent Na + , Ca 2+ and K + channels. Membrane depolarisation with high extracellular K + induces an increase of cytosolic [Ca 2+ ] and quantal catecholamine release.• Human glomus cells are responsive to hypoxia and hypoglycaemia, both of which induce an increase in cytosolic [Ca 2+ ] and transmitter release. Chemosensory responses of glomus cells are also preserved at an advanced age.• These findings on the cellular and molecular physiology of the CB provide novel perspectives for the systematic study of pathologies involving this organ in humans.Abstract The carotid body (CB) is the major peripheral arterial chemoreceptor in mammals that mediates the acute hyperventilatory response to hypoxia. The CB grows in response to sustained hypoxia and also participates in acclimatisation to chronic hypoxaemia. Knowledge of CB physiology at the cellular level has increased considerably in recent times thanks to studies performed on lower mammals, and rodents in particular. However, the functional characteristics of human CB cells remain practically unknown. Herein, we use tissue slices or enzymatically dispersed cells to determine the characteristics of human CB cells. The adult human CB parenchyma contains clusters of chemosensitive glomus (type I) and sustentacular (type II) cells as well as nestin-positive progenitor cells. This organ also expresses high levels of the dopaminotrophic glial cell line-derived neurotrophic factor (GDNF). We found that GDNF production and the number of progenitor and glomus cells were preserved in the CBs of human subjects of advanced age. qualitatively similar to those reported in lower mammals. These cells responded to hypoxia with an external Ca 2+ -dependent increase of cytosolic Ca 2+ and quantal catecholamine secretion, as reported for other mammalian species. Interestingly, human glomus cells are also responsive to hypoglycaemia and together these two stimuli can potentiate each other's effects. The chemosensory responses of glomus cells are also preserved at an advanced age. These new data on the cellular and molecular physiology of the CB pave the way for future pathophysiological studies involving this organ in humans.

Abstract-Urocortin has been shown to produce vasodilatation in several arteries, but the precise mechanism of its action is still poorly understood. Here we demonstrate the role of store operated Ca 2ϩ entry (SOCE) regulated by Ca 2ϩ -independent phospholipase A 2 (iPLA 2 ) in phenylephrine hydrochloride (PE)-induced vasoconstriction, and we present the first evidence that urocortin induces relaxation by the modulation of SOCE and iPLA 2 in rat coronary artery. Urocortin produces an endothelium independent relaxation, and its effect is concentrationdependent (IC 50 Ϸ4.5 nmol/L). We show in coronary smooth muscle cells (SMCs) that urocortin inhibits iPLA 2 activation, a crucial step for SOC channel activation, and prevents Ca 2ϩ influx evoked by the emptying of the stores via a cAMP and protein kinase A (PKA)-dependent mechanism. Lysophophatidylcholine and lysophosphatidylinositol, products of iPLA 2 , exactly mimic the effect of the depletion of the stores in presence of urocortin. Furthermore, we report that long treatment with urocortin downregulates iPLA 2 mRNA and proteins expression in rat coronary smooth muscle cells. In summary, we propose a new mechanism of vasodilatation by urocortin which involves the regulation of iPLA 2 and SOCE via the stimulation of a cAMP/PKA-dependent signal transduction cascade in rat coronary artery. Key Words: urocortin Ⅲ iPLA 2 Ⅲ vasoconstriction Ⅲ store operated Ca 2ϩ entry Ⅲ cAMP-PKA C oronary artery smooth muscle cells (SMCs) regulate vascular tone influencing perfusion of the heart, peripheral resistance, and as a consequence heart function. Agonist induces a contraction of vascular SMCs by a rise in cytosolic free Ca 2ϩ concentration 1,2 because of a rapid Ca 2ϩ release by InsP 3 from intracellular stores and a transmembrane Ca 2ϩ influx through L-type voltage-dependent Ca 2ϩ channels or nonvoltage-gated channels such as store-operated Ca 2ϩ (SOC) channels. The relative contribution of each channel depends on the smooth muscle type. [2][3][4] The use of selective inhibitors of sarcoplasmic reticulum Ca 2ϩ -ATPase pump, as thapsigargin (TG), to activate SOC channels not only increases Ca 2ϩ influx but also enhances tone in a variety of SMCs. 3,5 Recently we showed Ca 2ϩ -independent phospholipase A 2 (iPLA 2 ) to be a crucial determinant of storeoperated Ca 2ϩ entry (SOCE). We demonstrated that the emptying of the stores activated iPLA 2 and its lysophospholipid products opened the SOC channels in aortic SMCs and nonexcitable cells. 6 -8 Thus iPLA 2 became a potential physiological target for regulation and fine-tuning of SOCE by other signaling cascades in SMCs.A few years ago a new 40-aa peptide, urocortin, 9,10 related to corticotropin-releasing factor (CRF) was described as a new player in cardiac control, 11,12 and was proposed to protect cardiac myocytes during ischemia/reperfusion by downregulating iPLA 2 expression. 13,14 Urocortin also emerged as a potent vasodilator peptide, and its mechanism of action appears to be complex, eg, vasodilatation has been reported...