Effect of NMDA receptor ligands on mast cell histamine release, a reappraisal

Abstract

Natural polyamines have been proposed to induce histamine release from mast cells through a direct interaction with G proteins. Alternatively, the polyamine binding site of ionotropic N-methyl-D-aspartate (NMDA) receptors has been suggested as a target for spermine on mast cells. We reexamined both hypotheses. Incubation of rat peritoneal mast cells with spermine resulted in a concentration-dependent histamine release (EC50 270 microM). Incubation with NMDA receptor agonists, glutamate or NMDA, associated to the co-agonist glycine, did not induce secretion. Western blot experiments did not reveal NMDA R1, R2a, R2b or R2c subunit expression in rat peritoneal mast cell membranes. The NMDA receptor antagonist at the glycine site, L-689,560, did not modify, at relevant concentrations, the spermine-induced secretion. The NMDA receptor antagonists, ifenprodil and LY 235959, and the NMDA channel blocker, MK801, slightly inhibited, at high concentrations, the secretory effect of spermine. The polyamine arcaine, an antagonist of the NMDA receptor polyamine binding site, induced histamine secretion (EC50 350 microM). Both spermine- and arcaine-induced effects were independent upon extracellular calcium and were largely inhibited by treatment of mast cells with pertussis toxin or benzalkonium chloride. The response to spermine and arcaine was prevented by the hydrolysis of sialic acid residues of the cell surface by neuraminidase, and was restored by permeabilization of the plasma membrane with streptolysine-O, indicating that polyamines act intracellularly. These results confirm the involvement of pertussis toxin-sensitive G proteins in the secretory effect of polyamines and demonstrate the absence of NMDA receptors on rat peritoneal mast cells. Nonselective effects of some NMDA receptor ligands on mast cells cannot be excluded.

Imidazoline derivatives and agmatine induce histamine release from the rat stomach

“…Rothschild 1966) were found to release histamine from histamine-storing cells in cat skin preparations, in guinea-pig atria and lung and from human mast cells. Moreover, histamine release from rat peritoneal mast cells was also shown for putrescine, spermidine and spermine (Purcell et al 1994;Daeffler et al 1999), i.e. for compounds that are structurally closely related to agmatine.…”

Mast cells and histamine are involved in the neuronal damage observed in a quinolinic acid‐induced model of Huntington's disease

“…These data suggest that the inflammatory response plays an important role in the QUIN‐induced striatal damage, in which immune cells, like MCs, and inflammatory mediators, like HA, can potentiate the damage produced by the compound. Although it is yet not know how MCs are activated in this particular murine model, we assume that QUIN‐activation of MCs does not directly depend on the activation of NMDAR, since membranes purified from rat peritoneal MCs do not express NMDAR subunits NR1, NR2A, NR2B and NR2C (Daeffler et al, 1999). However, docking studies showed seven interaction sites between QUIN and VC1 domains of the Receptor for Advanced Glycation Endproducts (RAGE) (Bongarzone et al, 2017) and the activation of RAGE in rat peritoneal MCs triggers histamine secretion (Sick et al, 2010).…”

Pathophysiology of neonatal brain lesions: Lessons from animal models of excitotoxicity

“…Mast cell-derived histamine potentiates excitotoxicity in cultured hippocampal neurons [29]. On the other hand, the presence of NMDA receptors on mast cells remains controversial, although NMDA agonists induce mast-cell degranulation and NMDA antagonists (e.g., MK-801) block this effect [30,31]. Mast cells have been implicated in the pathophysiology of brain lesions associated with multiple sclerosis, Guillain-Barré syndrome or Gayet-Wernicke encephalopathy.…”