Role of STIM1 in neurodegeneration

STIM1 is an endoplasmic reticulum(ER) protein with a key role in Ca^(2+)mobilization. Due to its ability to act as an ER-intraluminal Ca^(2+) sensor, it regulates store-operated Ca^(2+) entry(SOCE), which is a Ca^(2+) influx pathway involved in a wide variety of signalling pathways in eukaryotic cells. Despite its important role in Ca^(2+) transport, current knowledge about the role of STIM1 in neurons is much more limited. Growing evidence supports a role for STIM1 and SOCE in the preservation of dendritic spines required for long-term potentiation and the formation of memory. In this regard, recent studies have demonstrated that the loss of STIM1, which impairs Ca^(2+) mobilization in neurons, risks cell viability and could be the cause of neurodegenerative diseases. The role of STIM1 in neurodegeneration and the molecular basis of cell death triggered by low levels of STIM1 are discussed in this review.

Sources of calcium in agonist-induced contraction of rat distal colon smooth muscle in vitro

AIM: To study the origin of calcium necessary for agonist-induced contraction of the distal colon in rats.METHODS: The change in intracellular calcium concentration ([Ca2+]i) evoked by elevating external Ca2+ was detected by fura 2/AM fluorescence. Contractile activity was measured with a force displacement transducer. Tension was continuously monitored and recorded using a Powerlab 4/25T data acquisition system with an ML110 bridge bioelectric physiographic amplifier.RESULTS: Store depletion induced Ca2+ influx had an effect on [Ca2+]i. In nominally Ca2+-free medium, the sarco-endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin (1 μmol/L) increased [Ca2+]i from 68 to 241 nmol/L, and to 458 (P < 0.01) and 1006 nmol/L (P < 0.01), respectively, when 1.5 mmol/L and 3.0 mmol/L extracellular Ca2+ was reintroduced. Furthermore, the change in [Ca2+]i was observed with verapamil (5 μmol/L), La3+ (1 mmol/L) or KCl (40 mmol/L) in the bathing solution. These channels were sensitive to La3+ (P < 0.01), insensitive to verapamil, and voltage independent. In isolated distal colons we found that in normal Krebs solution, contraction induced by acetylcholine (ACh) was partially inhibited by verapamil, and the inhibitory rate was 41% (P < 0.05). On the other hand, in Ca2+-free Krebs solution, ACh induced transient contraction due to Ca2+ release from the intracellular stores. The transient contraction lasted until the Ca2+ store was depleted. Restoration of extracellular Ca2+ in the presence of atropine produced contraction, mainly due to Ca2+ influx. Such contraction was not inhibited by verapamil, but was decreased by La3+ (50 μmol/L) from 0.96 to 0.72 g (P < 0.01). CONCLUSION: The predominant source of activator Ca2+ for the contractile response to agonist is extracellular Ca2+, and intracellular Ca2+ has little role to play in mediating excitation-contraction coupling by agonists in rat distal colon smooth muscle in vitro. The influx of extracellular Ca2+ is mainly mediated through voltage-, receptor- and store-operated Ca2+ channels, which can be used as an alternative to develop new drugs targeted on the dysfunction of digestive tract motility.