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AMPA receptors (AMPAr) mediate fast synaptic responses to glutamate and, when they lack the GluR[sub 2] subunit, are strongly Ca[sup 2+] permeable and may increase intracellular Ca[sup 2+] levels. Because hypoglossal motoneurons possess restricted ability to buffer internal Ca[sup 2+] and are vulnerable to Ca[sup 2+] excitotoxicity, we wondered if, in these cells, any significant Ca[sup 2+] influx could be generated via AMPAr activity. Using whole cell patch-clamp recording from neonatal rat hypoglossal motoneurons, we tested the AMPAr properties conferred by GluR[sub 2] subunits, namely Ca[sup 2+] permeability, current rectification and sensitivity to pentobarbital or to the subunit-specific channel blockers, IEM-1460 and IEM-1925. We recorded membrane currents generated by the agonist, kainate, and compared them with those obtained from hippocampal pyramidal neurons (expressing GluR[sub 2]-containing AMPAr) and from striatal giant aspiny or hippocampal interneurons (with GluR[sub 2]-lacking AMPAr). Ca[sup 2+] vs. Na[sup +] permeability of motoneuron AMPAr was relatively low (0.25 ± 0.05), although higher than that of pyramidal neurons. With intracellularly applied spermine, significant inward rectification was absent from motoneurons. These data indicated the prevalence of functional GluR[sub 2] subunits. However, the sensitivity of motoneuron AMPAr to pentobarbital did not differ from that of GluR[sub 2]-lacking AMPAr on interneurons. Motoneurons possessed sensitivity to IEM-1460 (IC[sub 50] = 90 ± 10 µM) approximately 10-fold lower than striatal interneurons, although 10-fold higher than hippocampal pyramidal cells. IEM-1925 also reduced the amplitude of excitatory synaptic currents in brainstem slice motoneurons. We hypothesize that hypoglossal motoneuron AMPAr (moderately Ca[sup 2+] permeable because they contain few GluR[sub 2] subunits) may contribute to intracellular Ca[sup 2+] rises especially if persistent AMPAr activation (or the... [ABSTRACT FROM AUTHOR]

Hyperforin, a bicyclic polyprenylated acylphloroglucinol derivative, is the main active principle of St. John's wort extract responsible for its antidepressive profile. Hyperforin inhibits the neuronal serotonin and norepinephrine uptake comparable to synthetic antidepressants. In contrast to synthetic antidepressants directly blocking neuronal amine uptake, hyperforin increases synaptic serotonin and norepinephrine concentrations by an indirect and yet unknown mechanism. Our attempts to identify the molecular target of hyperforin resulted in the identification of TRPC6. Hyperforin induced sodium and calcium entry as well as currents in TRPC6-expressing cells. Sodium currents and the subsequent breakdown of the membrane sodium gradients may be the rationale for the inhibition of neuronal amine uptake. The hyperforin-induced cation entry was highly specific and related to TRPC6 and was suppressed in cells expressing a dominant negative mutant of TRPC6, whereas phylogenetically related channels, i.e. TRPC3 remained unaffected. Furthermore, hyperforin induces neuronal axonal sprouting like NGF in a TRPC6-dependent manner. These findings support the role of TRPC channels in neurite extension and identify hyperforin as the first selective pharmacological tool to study TRPC6 function. Hyperforin integrates inhibition of neurotransmitter uptake and neurotrophic property by specific activation of TRPC6 and represents an interesting lead-structure for a new class of antidepressants. [ABSTRACT FROM AUTHOR]