Folate interactions with cerebral G proteins

Intracerebral folate injections produce convulsions and brain lesions, folic acid itself and tetrahydrofolate being more potent toxins than 5-methyltetrahydrofolate, the primary folate of mammalian extracellular fluids. Folates are known to excite neurons, by unknown mechanisms. Folates stimulate GTP binding and GTPase activity in slime molds. We observed folate stimulation of GTPS binding and inhibition of high affinity GTPase activity in rat brain membranes. Three fold stimulation of GTPS binding was observed in cerebellar membranes treated with 50 uM FA. Folic acid (FA), dihydrofolate (DHF) and tetrahydrofolate (THF) were much more potent than 5-methyltetrahydrofolate in this regard. The effect varies between brain regions and was greatest in cerebellar and hippocampal membranes. Folates inhibit GTPase activity, with DHF and FA being the most potent and maximum inhibition being to 33% of control values. We find high affinity guanine nucleotide sensitive binding of ³H]FA in cerebellar membranes, another response typical of G protein coupled membrane receptors. Folates were also shown to stimulate the release of ³H]GDP from brain membranes. These effects are seen in washed brain membranes and can not be explained by any known folate metabolic or coenzyme functions. They resemble the effects of cholera toxin, except for their reversibility. They may be relevant to known folate neuroexcitant effects of folates.