CADMIUM RAPIDLY AND IRREVERSIBLY BLOCKS PRESYNAPTIC PHOSPHOLIPASE C-LINKED METABOTROPIC GLUTAMATE RECEPTORS

Calcium ions (Cd2+) inhibit inositol phosphate (IF) formation elicited by glutamate (GLU) or K+ ions, without affecting carbachol (Carb)-ind uced IP response in 8-day-old rat forebrain synaptoneurosomes and syna ptosomes. On the contrary, Cd2+ was almost ineffective in blocking GLU - and K+-responses in hippocampal neurones in culture. The mechanism o f Cd2+ inhibition was thus examined in synaptoneurosomes. Extensive wa shing of synaptoneurosomes pretreated for 1, 5, 15, or 30 min by 100 m u M Cd2+ did not modify the inhibitory effect of Cd2+ on GLU-, K+- and A23187-evoked IP formation or its lack of effect on Carb response. Th e later addition of a high affinity Cd2+ chelator (100 mu M), N,N,N',N '-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) also did not reverse the inhibitory effect. TPEN, however, penetrates into synaptoneurosom es and efficiently displaces Cd2+ from the Fura-2-Cd2+ complex as show n by Fura-2 fluorescence recordings. TPEN is not easily removed from t he intracellular space, as demonstrated by its ability to still block Cd2+-induced Fura-2 fluorescence increase after extensive washing. Pre treatment of synaptoneurosomes by this chelator did not prevent Cd2+ i nhibition of GLU-induced IP formation. These data indicate that Cd2+ i ons rapidly, irreversibly and extracellularly inhibit GLU-elicited IP formation in synaptoneurosomes or synaptosomes, but not in hippocampal neurones in culture. It is speculated that Cd2+ ions could allow one to distinguish the activity of presynaptic metabotropic glutamate rece ptors (mGLURs) linked to phosphoinositide metabolism from that of mGLU Rs located postsynaptically. Copyright (C) 1996 Elsevier Science Ltd.