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P/Q-type Ca2+ Channels (p + ca2+_channel)
Selected AbstractsMonogenic migraine syndromes highlight novel drug targetsDRUG DEVELOPMENT RESEARCH, Issue 7 2007J. Jay Gargus Abstract In the post-genomic era, the paradigm for drug discovery has changed, as every gene may become a potential target. Genetic diseases provide a special window into gene target selection. This approach is being applied to migraine making use of the genes and mutations causing familial hemiplegic migraine (FHM). FHM is caused by missense mutations in CACNA1A, altering a neuronal P/Q Ca2+ channel, in ATP1A2, altering ,2 Na,K-ATPase, and in SCN1A, altering a neuronal sodium channel. These genes provide insights into migraine pathogenesis that likely extend to other forms of migraine as well. Since the three FHM genes are only co-expressed in neurons, FHM is a neuronal, not a vascular, disease and because they all encode ion transport proteins, FHM is a neuronal channelopathy,meaning meta-stable neuronal hyperexcitability is the substrate of migraine, much as it is for genetic epilepsy syndromes. This similarity is reinforced, since different mutations of all three FHM genes can produce seizure syndromes. This has implications for drug discovery in that seizure medications already known to modulate the FHM channel mechanisms warrant more targeted development, and that drugs targeted to vascular headaches, such as the historically effective triptans, or experimental botulinum toxin, may well work by similar nonvascular mechanisms. Finally, in model neurogenetic systems such as Caenorhabditis elegans, the FHM genes also provide both a comprehensive means to discover all genes involved in their signaling pathway,genes potentially involved in common forms of the disease, and an in vivo whole animal means to screen rapidly for novel therapeutics. Drug Dev Res 68:432,440, 2007. © 2008 Wiley-Liss, Inc. [source] ,-Aminobutyric acid-mediated regulation of the activity-dependent olfactory bulb dopaminergic phenotypeJOURNAL OF NEUROSCIENCE RESEARCH, Issue 10 2009Yosuke Akiba Abstract ,-Aminobutyric acid (GABA) regulates the proliferation and migration of olfactory bulb (OB) interneuron progenitors derived from the subventricular zone (SVZ), but the role of GABA in the differentiation of these progenitors has been largely unexplored. This study examines the role of GABA in the differentiation of OB dopaminergic interneurons using neonatal forebrain organotypic slice cultures prepared from transgenic mice expressing green fluorescent protein (GFP) under the control of the tyrosine hydroxylase (Th) gene promoter (ThGFP). KCl-mediated depolarization of the slices induced ThGFP expression. The addition of GABA to the depolarized slices further increased GFP fluorescence by inducing ThGFP expression in an additional set of periglomerular cells. These findings show that GABA promoted differentiation of SVZ-derived OB dopaminergic interneurons and suggest that GABA indirectly regulated Th expression and OB dopaminergic neuron differentiation through an acceleration of the maturation rate for the dopaminergic progenitors. Additional studies revealed that the effect of GABA on ThGFP expression required activation of L- and P/Q-type Ca2+ channels as well as GABAA and GABAB receptors. These voltage-gated Ca2+ channels and GABA receptors have previously been shown to be required for the coexpressed GABAergic phenotype in the OB interneurons. Together, these findings suggest that Th expression and the differentiation of OB dopaminergic interneurons are coupled to the coexpressed GABAergic phenotype and demonstrate a novel role for GABA in neurogenesis. © 2009 Wiley-Liss, Inc. [source] GABAB receptor modulation of excitatory and inhibitory synaptic transmission onto rat CA3 hippocampal interneuronsTHE JOURNAL OF PHYSIOLOGY, Issue 2 2003Saobo Lei Hippocampal stratum radiatum inhibitory interneurons receive glutamatergic excitatory innervation via the recurrent collateral fibers of CA3 pyramidal neurons and GABAergic inhibition from other interneurons. We examined both presynaptic- and postsynaptic-GABAB receptor-mediated responses at both synapse types. Postsynaptic GABAB receptor-mediated responses were absent in recordings from young (P16-18) but present in recordings from older animals (P30) suggesting developmental regulation. In young animals, the GABAB receptor agonist, baclofen, inhibited the amplitude of evoked EPSCs and IPSCs, an effect blocked by prior application of the selective antagonist CGP55845. Baclofen enhanced the paired-pulse ratio and coefficient of variation of evoked EPSCs and IPSCs, consistent with a presynaptic mechanism of regulation. In addition, baclofen reduced the frequency of miniature IPSCs but not mEPSCs. However, baclofen reduced the frequency of KCl-induced mEPSCs; an effect blocked by Cd2+, implicating presynaptic voltage-gated Ca2+ channels as a target for baclofen modulation. In contrast, although Cd2+ prevented the KCl-induced increase in mIPSC frequency, it failed to block baclofen's reduction of mIPSC frequency. Whereas N- and P/Q-types of Ca2+ channels contributed equally to GABAB receptor-mediated inhibition of EPSCs, more P/Q-type Ca2+ channels were involved in GABAB receptor-mediated inhibition of IPSCs. Finally, baclofen blocked the frequency-dependent depression of EPSCs and IPSCs, but was less effective at blocking frequency-dependent facilitation of EPSCs. Our results demonstrate that presynaptic GABAB receptors are expressed on the terminals of both excitatory and inhibitory synapses onto CA3 interneurons and that their activation modulates essential components of the release process underlying transmission at these two synapse types. [source] Electrophysiological and Neurochemical Evidence for Voltage-Dependent Ca2+ Channel Blockade by a Novel Neuroprotective Agent NS-7,BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2001Michiko Oka In rat dorsal root ganglion neurones, NS-7 (0.3,100 ,M) inhibited the whole-cell Ba2+ currents (IBa) in a voltage-dependent manner, in which the compound more potently blocked the IBa elicited from the holding potential of ,40 mV than that induced from ,80 mV. In slices of rat cerebral cortex, KCl-evoked nitric oxide synthesis was markedly inhibited by ,-conotoxin GVIA and ,-agatoxin IVA, but only slightly attenuated by nifedipine, suggesting that the response is mediated predominantly through activation of N-type and P/Q-type Ca2+ channels. NS-7 (1,100 ,M) inhibited the KCl-stimulated nitric oxide synthesis in a manner dependent on the intensity of the depolarizing stimuli. Moreover, weak but significant inhibitory effect of NS-7 was observed even after wash-out. Similar voltage-dependent inhibition of the KCl response was observed by a limited concentration (10 ,M) of verapamil. These findings indicate that NS-7 in several concentrations blocks Ca2+ channel in a voltage-dependent manner. [source] A comparison of Ca2+ channel blocking mode between gabapentin and verapamil: implication for protection against hypoxic injury in rat cerebrocortical slicesBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2003Michiko Oka The mode of Ca2+ channel blocking by gabapentin [1-(aminomethyl)cyclohexane acetic acid] was compared to those of other Ca2+ channel blockers, and the potential role of Ca2+ channel antagonists in providing protection against hypoxic injury was subsequently investigated in rat cerebrocortical slices. mRNA for the ,2, subunits of Ca2+ channels was found in rat cerebral cortex. Nitric oxide (NO) synthesis estimated from cGMP formation was enhanced by KCl stimulation, which was mediated primarily by the activation of N- and P/Q-type Ca2+ channels. Gabapentin blocked both types of Ca2+ channels, and preferentially reversed the response to 30 mM K+ stimulation compared with 50 mM K+ stimulation. In contrast, verapamil preferentially inhibited the response to depolarization by the higher concentration (50 mM) of K+. Gabapentin inhibited KCl-induced elevation of intracellular Ca2+ in primary neuronal culture. Hypoxic injury was induced in cerebrocortical slices by oxygen deprivation in the absence (severe injury) or presence of 3 mM glucose (mild injury). Gabapentin preferentially inhibited mild injury, while verapamil suppressed only severe injury. , -Conotoxin GVIA (, -CTX) and , -agatoxin IVA (, -Aga) were effective in both models. NO synthesis was enhanced in a manner dependent on the severity of hypoxic insults. Gabapentin reversed the NO synthesis induced by mild insults, while verapamil inhibited that elicited by severe insults. , -CTX and , -Aga were effective in both the cases. Therefore, the data suggest that gabapentin and verapamil cause activity-dependent Ca2+ channel blocking by different mechanisms, which are associated with their cerebroprotective actions and are dependent on the severity of hypoxic insults. British Journal of Pharmacology (2003) 139, 435,443. doi:10.1038/sj.bjp.0705246 [source] | |||||||||||||