Potential mechanisms underlying the atypical pharmacology of VIP effects in P5 mice

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In order to explain the observed characteristics of VPAC₂ receptors involved in VIP-induced neuroprotection in the P5 mouse, some hypotheses can be formulated: i) During some stages of brain development, the binding of VIP or PACAP to VPAC₂ receptors leads to activation of separate transduction pathways. This differential coupling could be secondary to VPAC₂ receptors dimerization (homo- or heterodimers) or to their interaction with larger oligomeric complexes, as demonstrated for other types of GPCRs [34]. A variant of this hypothesis would be a developmental change in the G proteins available for the receptor to couple to in the relevant cells. ii) VPAC receptors can dimerize with receptor activity modulating proteins (RAMPs), which leads to the modulation of cell signalling through a commutation of the coupling of a GPCR to different G proteins [35]. iii) An alternative hypothesis has been suggested by recent studies. A first study identified a deletion variant of the mouse VPAC₂ receptor in immune cells [36]. This natural deletion abrogates VIP-induced cAMP production without apparent alterations of expression or ligand binding. Secondly, Langer and Robberecht [37] showed that mutations in the proximal domain of the third intracellular loop of the VPAC₁ receptor reduced the capability of VIP to increase adenylate cyclase activity without any change in the calcium response, whereas mutations in the distal part of the loop markedly reduced the calcium increase and Gai coupling but only weakly reduced the adenylate cyclase activity. Based on these studies, we can hypothesize that a yet-to-be-identified substitution or deletion in the newborn mouse VPAC₂ receptor transcript, through RNA editing for instance, might be able to induce VIP specificity and modulate the coupling with different G proteins.