Absence of adenylyl cyclase 3 perturbs peripheral olfactory projections in mice.

A remarkable feature of peripheral olfactory projections in mammals is the convergence of axons from olfactory sensory neurons (OSNs) expressing the same odorant receptor (OR) into the same glomeruli. There is mounting evidence that the ORs play critical roles in glomerular formation. However, it remains unclear how the OR exerts its function of sorting axons into homogeneity. We and others have shown previously that activation of the G-protein/cAMP signaling cascade underlies glomerular formation. Here, we further investigated whether establishment of the mature glomerular array requires adenylyl cyclase 3 (AC3), a key component of the OR-mediated cAMP-dependent signaling cascade. We found robust AC3 expression in both OSN cilia and axons during the period of active glomerular formation in neonatal mice. Examination of OR-tagged mice in an AC3 knock-out background revealed that the absence of AC3 drastically and differentially perturbed the formation of several representative glomeruli. Furthermore, heterogeneous glomeruli innervated by axons of multiple OSN populations persisted in such mice well into adulthood. In addition, reproducible aberrations in axonal projections in AC3-/- mice appeared to correlate with the activation of specific OR loci, regardless of the expressed receptor sequence, suggesting that OR expression is but one factor in determining OSN axonal projections. Together, our results indicate that cAMP signaling is critical for axonal sorting and the establishment of axonal identity.

Solvent polarity effects and limited acid catalysis in rearrangements of model radicals for the methylmalonyl-CoA mutase- and isobutyryl-CoA mutase-catalyzed isomerization reactions.

The kinetics of reactions of models for the intermediate radicals formed in the methylmalonyl-CoA mutase- and isobutyryl-CoA mutase-catalyzed rearrangements were studied by laser flash photolysis methods. The aldehyde-containing model analogous to the propanal-3-yl radical reacted via 3-exo cyclization with rate constants that varied with solvent polarity (k in the range 2 x 105 to 1 x 107 s-1). The analogous methyl ketone-containing radical reacted 2 orders of magnitude less rapidly, and the ethylthiocarbonyl-containing radical analogue reacted too slowly for kinetic measurements. No acid catalysis was observed in acetic acid, but the CF3CO2H-complexed radicals reacted 1 order of magnitude faster than the uncomplexed radicals. The results indicate that catalysis of the 3-exo radical cyclizations of the radicals formed in the enzymes by hydrogen bonding to an acid, so-called "partial protonation", is not adequate for acceleration of the reactions to the point of kinetic competence. A dissociative mechanism for the radical rearrangements in nature is considered as an alternative.