Endothelin‐Mediated Calcium Response and Inositol 1,4,5‐Trisphosphate Release in Neuroblastoma‐Glioma Hybrid Cells (NG108‐15): Cross Talk with ATP and Bradykinin

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Abstract
Addition of endothelins (ETs) to neuroblastomaglioma hybrid cells (NG108‐15) induced increases in cytosolic free Ca2+ ([Ca2+]i) levels of labeled inositol monophosphates and inositol 1,4,5‐trisphosphate [Ins(1,4,5)P3]. The increases in [Ca2+]i elicited by the three ETs (ET‐1, ET‐2, and ET‐3) were transient and did not show a sustained phase. Chelating extracellular Ca2+ in the medium by adding excess EGTA decreased the ET‐mediated Ca2+ response by 40‐50%. This result indicates that a substantial portion of the increase in [Ca2+]i was due to influx from an extracellular source. However, the increase in [Ca2+]i was not affected by verapamil or nifedipine (10−5M). A rank order potency of ET‐1 ET‐2 ET‐3 is shown for the stimulated increase in [Ca2+]i, as well as labeled inositol phosphates, in these cells. ATP (10−4M) and bradykinin (10−7M) also induced the increases in [Ca2+]i and Ins(1,4,5)P3 in NG108‐15 cells, albeit to a different extent. When compared at 10−7M, bradykinin elicited a five‐ to sixfold higher increase in the level of Ins(1,4,5)P3, but less than a twofold higher increase in [Ca2+]i than those induced by ET‐1. Additive increases in both Ins(1,4,5)P3 and [Ca2+]i were observed when ET‐1, ATP, and bradykinin were added to the cells in different combinations, suggesting that each receptor agonist is responsible for the hydrolysis of a pool of polyphosphoinositide within the membrane. ET‐1 exhibited homologous desensitization of the Ca2+ response, but partial heterologous desensitization to the Ca2+ response elicited by ATP. On the contrary, ET‐1 did not desensitize the response elicited by bradykinin, although bradykinin exhibited complete heterologous desensitization to the response elicited by ET‐1. Taken together, these results illustrate that, in NG108‐15 cells, a considerable amount of receptor cross talk occurs between ET and other receptors that transmit signals through the polyphosphoinositide pathway.

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