The basic secretagogue compound 48/80 activates G proteins indirectlyviastimulation of phospholipase D–lysophosphatidic acid receptor axis and 5‐HT1Areceptors in rat brain sections

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Abstract
The basic secretagogues, such as compound 48/80 (c48/80) and mastoparans, are widely used histamine‐releasing agents and their mechanism of action is commonly attributed to a direct, receptor‐bypassing property to activate the Gi/oclass of G proteins. We tested here whether c48/80 could directly stimulate [35S]guanosine‐5′‐[γ‐thio]triphosphate ([35S]GTPγS) binding to rat brain sections in an attempt to visualize the entire signaling pool of Gi/oin its native neuroanatomical context. Instead of direct Gi/oactivation, c48/80 (100 μg ml−1) from various suppliers stimulated brain phospholipase D (PLD) activity, leading to the generation of endogenous phospholipids capable of activating brain white matter‐enriched, Gi/o‐coupled lysophosphatidic acid (LPA) receptors. This response was sensitive to 1‐butanol and was potently reversed by the LPA1/LPA3receptor‐selective antagonist Ki16425 (IC5059±13 nM, mean±s.e.m.), and showed age‐dependent decline, closely reflecting known developmental regulation of the PLD–LPA1receptor axis in the CNS. In addition, c48/80 was found to modestly activate hippocampal 5‐HT1Areceptors in a pH‐dependent and antagonist‐sensitive manner. Consistent with the lack of direct Gi/o‐activating properties in brain sections, c48/80 showed no activity in classical membrane [35S]GTPγS binding assays. Instead, c48/80 from one particular manufacturer elicited non‐specific effect in these assays, therefore challenging the previous interpretations regarding the compound's ability to activate G proteins directly. We conclude that c48/80 is not a receptor‐bypassing general G protein activator but rather activates PLD, leading to generation of endogenous LPA receptor‐activating phospholipids. This property may also contribute to the compound's ability to release histamine from mast cells. British Journal of Pharmacology(2006)147, 596–606. doi:10.1038/sj.bjp.0706671

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