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Activation of Store-Operated Ca²⁺ Channels in Trabecular Meshwork Cells

¹From the Laboratory of Neurophysiology, Faculty of Medicine, and the ²Biophysics Unit, Department of Physiological Sciences I-Institute of Biomedical Investigations August Pi i Sunyer, School of Medicine, University of Barcelona, Spain.

PURPOSE. In nonexcitable cells, G_q-coupled membrane receptor activation induces a biphasic increase in intracellular calcium ([Ca²⁺]_i) expressed as an initial IP₃-dependent release from intracellular stores followed by a sustained Ca²⁺ influx from the extracellular space that involves store-operated Ca²⁺ channels (SOCs). In trabecular meshwork (TM) cells, contractile agonists such as bradykinin (BK) and endothelin-1 (ET-1) induce this type of Ca²⁺ signaling. Given that trabecular outflow is modified by tissue contractility, the authors characterized SOCs and studied their participation in TM cell contractility.

METHODS. [Ca²⁺]_i was measured in cultured bovine TM cells loaded with Fura-2. Ca²⁺ currents were recorded using the patch clamp technique. Cell contractility measurements were assessed by traction microscopy.

RESULTS. BK and ET-1 activate a store-operated Ca²⁺ entry that was greatly reduced in the absence of extracellular Ca²⁺ or by preincubation with SOC blocker 2-APB or SKF96365. Store-operated Ca²⁺ currents were also activated by intracellular dialysis with IP₃ + EGTA or after stimulation with thapsigargin. Electrophysiological characterization supports the presence of Ca²⁺ release-activated Ca²⁺ channels (CRACs) and nonselective cation channels, of which TRPC1 and TRPC4 channels may be candidate TRPs detected in TM cells. Extracellular Ca²⁺ entry through SOCs is not required for TM cell contraction in response to BK or ET-1, but it modulates this process.

CONCLUSIONS. Extracellular Ca²⁺ entry in TM cells in response to agonist stimulation and store-depletion is mediated by the activation of SOCs, which do not contribute to cell contraction but which may activate regulatory mechanisms to prevent excessive contraction. CRAC and TRPC channels involved represent interesting modulators of TM function to improve aqueous humor outflow.