The basic secretagogue compound 48/80 activates G proteins indirectly via stimulation of phospholipase D-lysophosphatidic acid receptor axis and 5-HT1A receptors in rat brain sections
Palomaki, VAB; Laitinen, JT
HERO ID
1461031
Reference Type
Journal Article
Year
2006
Language
English
PMID
| HERO ID | 1461031 |
|---|---|
| In Press | No |
| Year | 2006 |
| Title | The basic secretagogue compound 48/80 activates G proteins indirectly via stimulation of phospholipase D-lysophosphatidic acid receptor axis and 5-HT1A receptors in rat brain sections |
| Authors | Palomaki, VAB; Laitinen, JT |
| Journal | British Journal of Pharmacology |
| Volume | 147 |
| Issue | 6 |
| Page Numbers | 596-606 |
| 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 G(i/o) class of G proteins. We tested here whether c48/80 could directly stimulate [(35)S]guanosine-5'-[gamma-thio]triphosphate ([(35)S]GTPgammaS) binding to rat brain sections in an attempt to visualize the entire signaling pool of G(i/o) in its native neuroanatomical context. Instead of direct G(i/o) activation, c48/80 (100 microg 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, G(i/o)-coupled lysophosphatidic acid (LPA) receptors. This response was sensitive to 1-butanol and was potently reversed by the LPA(1)/LPA(3) receptor-selective antagonist Ki16425 (IC(50) 59+/-13 nM, mean+/-s.e.m.), and showed age-dependent decline, closely reflecting known developmental regulation of the PLD-LPA(1) receptor axis in the CNS. In addition, c48/80 was found to modestly activate hippocampal 5-HT(1A) receptors in a pH-dependent and antagonist-sensitive manner. Consistent with the lack of direct G(i/o)-activating properties in brain sections, c48/80 showed no activity in classical membrane [(35)S]GTPgammaS 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. |
| Doi | 10.1038/sj.bjp.0706671 |
| Pmid | 16415902 |
| Wosid | WOS:000236531300003 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Source: Web of Science WOS:000236531300003 |
| Is Public | Yes |
| Language Text | English |
| Keyword | compound 48/80; phospholipase D; lysophosphatidic acid; Ki16425; [S-35]GTP gamma S binding assay; 5-HT1A receptor |