Puberty is characterized by mood swings and anxiety, often produced by stress. Here, we show that THP (allopregnanolone), a steroid released by stress, increases anxiety in pubertal female mice, a reversal of its well-known anxiety-reducing effect in adults. Anxiety is regulated by GABAergic inhibition in limbic circuits. Although this inhibition is increased by THP before puberty and in adults, THP reduced tonic inhibition of CA1 hippocampal pyramidal cells at puberty, leading to increased excitability. This paradoxical effect of THP was due to inhibition of α4βδ GABA A receptors. These receptors are normally expressed at very low levels, but at puberty, their expression was increased in CA1 hippocampus where they generated outward currents. THP also decreased outward current at recombinant α4β2δ receptors, an effect dependent on arginine 353 in the α4 subunit, a putative Cl − modulatory site. Thus, inhibition of α4β2δ GABA A receptors by THP provides a mechanism for anxiety at puberty.The onset of puberty is associated with increases in emotional reactivity and anxiety 1,2 . Responses to stressful events are amplified 3 , and anxiety and panic disorder first emerge at this time 2 , twice as likely to occur in girls than in boys 2 . Few studies have addressed the biological basis of this important issue, although suicide risk increases in adolescence, despite the use of adult-based medical strategies 2 .The GABA A receptor plays a pivotal role in the generation of anxiety 4 . This receptor is the target for endogenous steroids such as THP (3α-OH-5α [β]-pregnan-20-one or [allo] pregnanolone), which increase GABA-gated currents at physiological concentrations 5 of the steroid. THP is a metabolite of the ovarian/adrenal steroid progesterone, but is also formed in the brain as a compensatory response to stress 6 . In adults, THP potently reduces anxiety in humans 7 , an effect seen in animal models with direct administration into the dorsal CA1 hippocampus 8 , part of the limbic system that regulates emotion. It is generally accepted that * Correspondence and requests for materials should be addressed to S.S.Smith, Dept. of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203 USA; phone: 718-270-2226; FAX: 718-270-3103; email: Sheryl.smith@downstate NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the GABA-enhancing action of THP underlies its well-known anxiety-reducing effect in adults, which is similar to other GABA-enhancing drugs such as the benzodiazepines.GABA A receptors are pentamers formed predominantly of 2α, 2β and 1γ subunits 9 which gate a Cl − current and produce most fast synaptic inhibition in the brain. Substitution of the δ subunit for γ2 yields a receptor with the highest sensitivity to steroids such as THP 10-12 . These highly sensitive δ-GABA A receptors are extrasynaptic 13 , and mediate tonic rather than synaptic inhibition in areas such as dentate gyrus 14 . Thus, THP and related steroids enhance inhibition h...
Endogenous polyamines, in particular spermine, have been found to cause block and modulation of a number of types of ion channel. Intracellular spermine is responsible for intrinsic gating and rectification of strong inward rectifier K+ channels by directly plugging the ion channel pore. These K+ channels control the resting membrane potential in both excitable and non-excitable cells, and control the excitability threshold in neurons and muscle cells. Intracellular spermine causes inward rectification at some subtypes of Ca2+-permeable glutamate receptors in the central nervous system, again by plugging the receptor channel pore, and spermine can even permeate the ion channel of these receptors. Extracellular spermine has multiple effects at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptor, including stimulation that increases the size of NMDA receptor currents, and voltage-dependent block. A number of polyamine-conjugated arthropod toxins and synthetic polyamine analogues are potent antagonists of glutamate receptors, and represent new tools with which to study these receptors. Interactions of polyamines with other types of cation channels have been reported. This area of research represents a new biology and a new pharmacology of polyamines.
A large number of structurally diverse compounds act as openchannel blockers of NMDA receptors. They may share discrete or overlapping binding sites within the channel. In this study, the effects of mutations in and around the membrane-spanning and pore-forming regions of NMDA receptor subunits were studied with three blockers, MK-801, memantine, and TB-3-4, using recombinant NMDA receptors expressed in Xenopus laevis oocytes. Mutations at the critical asparagine residues in the M2 loop of NR1 and NR2B and at a tryptophan residue in M2 of NR2B reduced block by MK-801, memantine, and TB-3-4. Mutations at residues in the pre-M1, M1, M3, post-M3, and post-M4 regions had differential effects on the three blockers. Many mutations in these regions reduced block by MK-801 and TB-3-4 but had no effect on block by memantine. The differential effects on block by memantine and MK-801 are unlikely to be caused by differences in the size of these blockers. Benzyl rings in MK-801 and TB-3-4 may make hydrophobic interactions with aromatic and hydrophobic amino acid residues in the pore. Some mutations in the pre-M1 and M3 regions generated constitutively open channels, characterized by large holding currents. The effects of the various mutants are discussed in the context of models based on the known structure of the pore of the KcsA potassium channel and on previous studies dealing with solvent accessible residues in NMDA receptor subunits as determined by modification after cysteine mutagenesis.
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