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Lary C Walker - One of the best experts on this subject based on the ideXlab platform.
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Calcium channel alpha2 delta type 1 subunit is the major binding protein for pregabalin in neocortex hippocampus amygdala and spinal cord an ex vivo autoradiographic study in alpha2 delta type 1 genetically modified mice
Brain Research, 2006Co-Authors: Feng Bian, Zheng Li, James Offord, Duff M Davis, Julie Mccormick, Charles Taylor, Lary C WalkerAbstract:Abstract Pregabalin is a synthetic amino acid compound effective in clinical trials for the treatment of post-herpetic neuralgia, diabetic peripheral neuropathy, generalized anxiety disorder and adjunctive therapy for partial seizures of epilepsy. However, the mechanisms by which pregabalin exerts its therapeutic effects are not yet completely understood. In vitro studies have shown that pregabalin binds with high affinity to the alpha2-delta (α2-δ) subunits (Type 1 and 2) of Voltage-Gated Calcium Channels. To assess whether α2-δ Type 1 is the major central nervous system (CNS) binding protein for pregabalin in vivo, a mutant mouse with an arginine-to-alanine mutation at amino acid 217 of the α2-δ Type 1 protein (R217A mutation) was generated. Previous site-directed mutagenesis studies revealed that the R217A mutation dramatically reduces α2-δ 1 binding to pregabalin in vitro. In this autoradiographic analysis of R217A mice, we show that the mutation to α2-δ Type 1 substantially reduces specific pregabalin binding in CNS regions that are known to preferentially express the α2-δ Type 1 protein, notably the neocortex, hippocampus, basolateral amygdala and spinal cord. In mutant mice, pregabalin binding was robust throughout regions where the α2-δ Type 2 subunit mRNA is abundant, such as cerebellum. These findings, in conjunction with prior in vitro binding data, provide evidence that the α2-δ Type 1 subunit of Voltage-Gated Calcium Channels is the major binding protein for pregabalin in CNS. Moreover, the distinct localization of α2-δ Type 1 and mutation-resistant binding (assumed to be α2-δ Type 2) in brain areas subserving different functions suggests that identification of subunit-specific ligands could further enhance pharmacologic specificity.
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Calcium channel alpha2 delta type 1 subunit is the major binding protein for pregabalin in neocortex hippocampus amygdala and spinal cord an ex vivo autoradiographic study in alpha2 delta type 1 genetically modified mice
Brain Research, 2006Co-Authors: Feng Bian, James Offord, Duff M Davis, Julie Mccormick, Charles Taylor, Lary C WalkerAbstract:Pregabalin is a synthetic amino acid compound effective in clinical trials for the treatment of post-herpetic neuralgia, diabetic peripheral neuropathy, generalized anxiety disorder and adjunctive therapy for partial seizures of epilepsy. However, the mechanisms by which pregabalin exerts its therapeutic effects are not yet completely understood. In vitro studies have shown that pregabalin binds with high affinity to the alpha(2)-delta (alpha(2)-delta) subunits (Type 1 and 2) of Voltage-Gated Calcium Channels. To assess whether alpha(2)-delta Type 1 is the major central nervous system (CNS) binding protein for pregabalin in vivo, a mutant mouse with an arginine-to-alanine mutation at amino acid 217 of the alpha(2)-delta Type 1 protein (R217A mutation) was generated. Previous site-directed mutagenesis studies revealed that the R217A mutation dramatically reduces alpha(2)-delta 1 binding to pregabalin in vitro. In this autoradiographic analysis of R217A mice, we show that the mutation to alpha(2)-delta Type 1 substantially reduces specific pregabalin binding in CNS regions that are known to preferentially express the alpha(2)-delta Type 1 protein, notably the neocortex, hippocampus, basolateral amygdala and spinal cord. In mutant mice, pregabalin binding was robust throughout regions where the alpha(2)-delta Type 2 subunit mRNA is abundant, such as cerebellum. These findings, in conjunction with prior in vitro binding data, provide evidence that the alpha(2)-delta Type 1 subunit of Voltage-Gated Calcium Channels is the major binding protein for pregabalin in CNS. Moreover, the distinct localization of alpha(2)-delta Type 1 and mutation-resistant binding (assumed to be alpha(2)-delta Type 2) in brain areas subserving different functions suggests that identification of subunit-specific ligands could further enhance pharmacologic specificity.
Bethan Lang - One of the best experts on this subject based on the ideXlab platform.
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cerebellar ataxia in non paraneoplastic lambert eaton myasthenic syndrome
Journal of the Neurological Sciences, 2008Co-Authors: Paulo Jose Lorenzoni, Bethan Lang, Rosana Herminia Scola, Helio A G Teive, Pedro Andre Kowacs, Lineu Cesar WerneckAbstract:Abstract Lambert–Eaton myasthenic syndrome (LEMS) is an immune-mediated disorder of the neuromuscular junction that rarely is associated with cerebellar ataxia (CA). We describe two patients with non-paraneoplastic LEMS associated with CA who showed high levels of anti-P/Q-type Voltage-Gated Calcium Channels antibodies in the serum and cerebrospinal fluid, and reduced CMAP with increment after brief maximum voluntary contraction in electrophysiological studies. We suggest that LEMS should be considered in the differential diagnosis of patients with CA.
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the action of lambert eaton myasthenic syndrome immunoglobulin g on cloned human voltage gated Calcium Channels
Muscle & Nerve, 2002Co-Authors: Ashwin Pinto, J Newsomdavis, Kazuo Iwasa, Claire Newland, Bethan LangAbstract:In the Lambert–Eaton myasthenic syndrome (LEMS), immunoglobulin G (IgG) autoantibodies to presynaptic Voltage-Gated Calcium Channels (VGCCs) at the neuromuscular junction lead to a reduction in nerve-evoked release of neurotransmitter and muscle weakness. We have examined the action of LEMS IgGs on cloned human VGCCs stably expressed in transfected human embryonic kidney (HEK293) cell lines: 10–13 (α1A-2, α2bδ, β4a) and C2D7 (α1B-1 , α2bδ, β1b). All LEMS IgGs studied showed surface binding to [125I]-ω-CTx-MVIIC-labeled VGCCs in the α1A cell line and two of six IgGs showed surface binding to [125I]-ω-CTx-GVIA-labeled VGCCs in the α1B cell line. We next studied the effect of LEMS IgGs (2 mg/ml) on whole-cell Calcium currents in the α1A and α1B cell lines. Overnight treatment of α1A (10–13) cells with LEMS IgGs led to a significant reduction in peak current density without alteration of the current–voltage relationship or the voltage dependence of steady-state inactivation. In contrast, LEMS IgGs did not reduce peak current density in the α1B cell line. Overall these data demonstrate the specificity of LEMS IgGs for the α1A cell line and suggest that LEMS IgGs bind to and downregulate VGCCs in this cell line. Although several LEMS IgGs can be shown to bind to the α1B (C2D7) cell line, no functional effects were seen on this channel. © 2002 Wiley Periodicals, Inc. Muscle Nerve 25: 000–000, 2002
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effect of lambert eaton myasthenic syndrome antibodies on autonomic neurons in the mouse
Annals of Neurology, 1997Co-Authors: Sally A Waterman, Bethan Lang, J NewsomdavisAbstract:Somatic muscle weakness and autonomic symptoms characterize the autoimmune Lambert-Eaton myasthenic syndrome (LEMS). The former results from IgG autoantibody-mediated down-regulation of P/Q-type Voltage-Gated Calcium Channels at motor nerve terminals and consequent reduction in acetylcholine release; the basis for the autonomic symptoms is unknown. Using omega-conotoxins GVIA and MVIIC and omega-agatoxin IVA that block N-, Q-, and P-type Channels, we investigated ex vivo the Calcium Channels subserving transmitter release from postganglionic parasympathetic neurons in the bladder and from postganglionic sympathetic neurons in the vas deferens of mice injected with IgG from LEMS patients or from controls. Calcium influx through N-, P-, and Q-type Channels subserved transmitter release from parasympathetic and sympathetic neurons in control mice. In test mice, the component of transmitter release subserved by P-type Channels was abolished by four of four LEMS IgG preparations, that subserved by Q-type Channels was significantly reduced by three, and that subserved by N-type Channels by one. Thus, LEMS IgG impairs transmitter release from parasympathetic and sympathetic neurons through down-regulation of one or more subtypes of Voltage-Gated Calcium Channels. The results suggest that antibody-mediated interference with specific ion channel function may also underlie autonomic dysfunction occurring in other autoimmune diseases.
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an improved diagnostic assay for lambert eaton myasthenic syndrome
Journal of Neurology Neurosurgery and Psychiatry, 1995Co-Authors: Masakatsu Motomura, Angela Vincent, I Johnston, Bethan Lang, J NewsomdavisAbstract:A new immunoprecipitation assay has been established for detecting antibodies to Voltage-Gated Calcium Channels (VGCCs) in Lambert-Eaton myasthenic syndrome (LEMS), using 125I-omega-conotoxin MVIIC, which binds to P-type VGCCs, to label extracts of human cerebellum. Fifty six of 66 serum samples (85%) from patients with clinically and electrophysiologically definite LEMS were positive for the presence of VGCC antibodies, defined as a titre > 3 SD above the mean for the healthy controls (n = 10). All disease controls (n = 40) were negative. This sensitive immunoassay should prove valuable in the diagnosis of LEMS.
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Calcium channel autoantibodies in the lambert eaton myasthenic syndrome
Annals of Neurology, 1991Co-Authors: K Leys, I Johnston, Bethan Lang, J NewsomdavisAbstract:We have tested 36 patients with the Lambert‐Eaton myasthenic syndrome for serum antibodies to voltage‐gated Calcium Channels by using an immunoprecipitation assay with [125I] ω‐conotoxin–labeled voltage‐gated Calcium Channels extracted from a human neuroblastoma cell line, SKN‐SH. Forty‐four percent of these patients had significant levels of antibody (30–1,466 pM) compared with healthy control individuals (< 15 pM). The incidence of positive sera in patients without associated small cell lung carcinoma (61%) was greater than in those patients with small cell lung carcinoma (28%). Results correlated strongly with results obtained using voltage‐gated Calcium Channels extracted from the small cell lung carcinoma line, MAR5. Anti–voltage‐gated Calcium channel antibody titers did not correlate with disease severity across individuals, but longitudinal studies in 2 patients receiving immunosuppressive therapy showed a clear inverse relation between antibody titer and an electromyographic index of disease severity. The incidence of positive sera among patients with other neurological disorders was not significant, but 8 of 12 patients with rheumatoid arthritis or systemic lupus erythematosus had raised titers (30–82 pM). We conclude that the antibodies detected in this assay are heterogeneous and that some of them are likely to be implicated in this disorder of neuromuscular transmission. The assay should prove useful as an additional diagnostic aid in patients with Lambert‐Eaton myasthenic syndrome.
J Newsomdavis - One of the best experts on this subject based on the ideXlab platform.
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the action of lambert eaton myasthenic syndrome immunoglobulin g on cloned human voltage gated Calcium Channels
Muscle & Nerve, 2002Co-Authors: Ashwin Pinto, J Newsomdavis, Kazuo Iwasa, Claire Newland, Bethan LangAbstract:In the Lambert–Eaton myasthenic syndrome (LEMS), immunoglobulin G (IgG) autoantibodies to presynaptic Voltage-Gated Calcium Channels (VGCCs) at the neuromuscular junction lead to a reduction in nerve-evoked release of neurotransmitter and muscle weakness. We have examined the action of LEMS IgGs on cloned human VGCCs stably expressed in transfected human embryonic kidney (HEK293) cell lines: 10–13 (α1A-2, α2bδ, β4a) and C2D7 (α1B-1 , α2bδ, β1b). All LEMS IgGs studied showed surface binding to [125I]-ω-CTx-MVIIC-labeled VGCCs in the α1A cell line and two of six IgGs showed surface binding to [125I]-ω-CTx-GVIA-labeled VGCCs in the α1B cell line. We next studied the effect of LEMS IgGs (2 mg/ml) on whole-cell Calcium currents in the α1A and α1B cell lines. Overnight treatment of α1A (10–13) cells with LEMS IgGs led to a significant reduction in peak current density without alteration of the current–voltage relationship or the voltage dependence of steady-state inactivation. In contrast, LEMS IgGs did not reduce peak current density in the α1B cell line. Overall these data demonstrate the specificity of LEMS IgGs for the α1A cell line and suggest that LEMS IgGs bind to and downregulate VGCCs in this cell line. Although several LEMS IgGs can be shown to bind to the α1B (C2D7) cell line, no functional effects were seen on this channel. © 2002 Wiley Periodicals, Inc. Muscle Nerve 25: 000–000, 2002
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effect of lambert eaton myasthenic syndrome antibodies on autonomic neurons in the mouse
Annals of Neurology, 1997Co-Authors: Sally A Waterman, Bethan Lang, J NewsomdavisAbstract:Somatic muscle weakness and autonomic symptoms characterize the autoimmune Lambert-Eaton myasthenic syndrome (LEMS). The former results from IgG autoantibody-mediated down-regulation of P/Q-type Voltage-Gated Calcium Channels at motor nerve terminals and consequent reduction in acetylcholine release; the basis for the autonomic symptoms is unknown. Using omega-conotoxins GVIA and MVIIC and omega-agatoxin IVA that block N-, Q-, and P-type Channels, we investigated ex vivo the Calcium Channels subserving transmitter release from postganglionic parasympathetic neurons in the bladder and from postganglionic sympathetic neurons in the vas deferens of mice injected with IgG from LEMS patients or from controls. Calcium influx through N-, P-, and Q-type Channels subserved transmitter release from parasympathetic and sympathetic neurons in control mice. In test mice, the component of transmitter release subserved by P-type Channels was abolished by four of four LEMS IgG preparations, that subserved by Q-type Channels was significantly reduced by three, and that subserved by N-type Channels by one. Thus, LEMS IgG impairs transmitter release from parasympathetic and sympathetic neurons through down-regulation of one or more subtypes of Voltage-Gated Calcium Channels. The results suggest that antibody-mediated interference with specific ion channel function may also underlie autonomic dysfunction occurring in other autoimmune diseases.
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an improved diagnostic assay for lambert eaton myasthenic syndrome
Journal of Neurology Neurosurgery and Psychiatry, 1995Co-Authors: Masakatsu Motomura, Angela Vincent, I Johnston, Bethan Lang, J NewsomdavisAbstract:A new immunoprecipitation assay has been established for detecting antibodies to Voltage-Gated Calcium Channels (VGCCs) in Lambert-Eaton myasthenic syndrome (LEMS), using 125I-omega-conotoxin MVIIC, which binds to P-type VGCCs, to label extracts of human cerebellum. Fifty six of 66 serum samples (85%) from patients with clinically and electrophysiologically definite LEMS were positive for the presence of VGCC antibodies, defined as a titre > 3 SD above the mean for the healthy controls (n = 10). All disease controls (n = 40) were negative. This sensitive immunoassay should prove valuable in the diagnosis of LEMS.
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Calcium channel autoantibodies in the lambert eaton myasthenic syndrome
Annals of Neurology, 1991Co-Authors: K Leys, I Johnston, Bethan Lang, J NewsomdavisAbstract:We have tested 36 patients with the Lambert‐Eaton myasthenic syndrome for serum antibodies to voltage‐gated Calcium Channels by using an immunoprecipitation assay with [125I] ω‐conotoxin–labeled voltage‐gated Calcium Channels extracted from a human neuroblastoma cell line, SKN‐SH. Forty‐four percent of these patients had significant levels of antibody (30–1,466 pM) compared with healthy control individuals (< 15 pM). The incidence of positive sera in patients without associated small cell lung carcinoma (61%) was greater than in those patients with small cell lung carcinoma (28%). Results correlated strongly with results obtained using voltage‐gated Calcium Channels extracted from the small cell lung carcinoma line, MAR5. Anti–voltage‐gated Calcium channel antibody titers did not correlate with disease severity across individuals, but longitudinal studies in 2 patients receiving immunosuppressive therapy showed a clear inverse relation between antibody titer and an electromyographic index of disease severity. The incidence of positive sera among patients with other neurological disorders was not significant, but 8 of 12 patients with rheumatoid arthritis or systemic lupus erythematosus had raised titers (30–82 pM). We conclude that the antibodies detected in this assay are heterogeneous and that some of them are likely to be implicated in this disorder of neuromuscular transmission. The assay should prove useful as an additional diagnostic aid in patients with Lambert‐Eaton myasthenic syndrome.
Feng Bian - One of the best experts on this subject based on the ideXlab platform.
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Calcium channel alpha2 delta type 1 subunit is the major binding protein for pregabalin in neocortex hippocampus amygdala and spinal cord an ex vivo autoradiographic study in alpha2 delta type 1 genetically modified mice
Brain Research, 2006Co-Authors: Feng Bian, Zheng Li, James Offord, Duff M Davis, Julie Mccormick, Charles Taylor, Lary C WalkerAbstract:Abstract Pregabalin is a synthetic amino acid compound effective in clinical trials for the treatment of post-herpetic neuralgia, diabetic peripheral neuropathy, generalized anxiety disorder and adjunctive therapy for partial seizures of epilepsy. However, the mechanisms by which pregabalin exerts its therapeutic effects are not yet completely understood. In vitro studies have shown that pregabalin binds with high affinity to the alpha2-delta (α2-δ) subunits (Type 1 and 2) of Voltage-Gated Calcium Channels. To assess whether α2-δ Type 1 is the major central nervous system (CNS) binding protein for pregabalin in vivo, a mutant mouse with an arginine-to-alanine mutation at amino acid 217 of the α2-δ Type 1 protein (R217A mutation) was generated. Previous site-directed mutagenesis studies revealed that the R217A mutation dramatically reduces α2-δ 1 binding to pregabalin in vitro. In this autoradiographic analysis of R217A mice, we show that the mutation to α2-δ Type 1 substantially reduces specific pregabalin binding in CNS regions that are known to preferentially express the α2-δ Type 1 protein, notably the neocortex, hippocampus, basolateral amygdala and spinal cord. In mutant mice, pregabalin binding was robust throughout regions where the α2-δ Type 2 subunit mRNA is abundant, such as cerebellum. These findings, in conjunction with prior in vitro binding data, provide evidence that the α2-δ Type 1 subunit of Voltage-Gated Calcium Channels is the major binding protein for pregabalin in CNS. Moreover, the distinct localization of α2-δ Type 1 and mutation-resistant binding (assumed to be α2-δ Type 2) in brain areas subserving different functions suggests that identification of subunit-specific ligands could further enhance pharmacologic specificity.
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Calcium channel alpha2 delta type 1 subunit is the major binding protein for pregabalin in neocortex hippocampus amygdala and spinal cord an ex vivo autoradiographic study in alpha2 delta type 1 genetically modified mice
Brain Research, 2006Co-Authors: Feng Bian, James Offord, Duff M Davis, Julie Mccormick, Charles Taylor, Lary C WalkerAbstract:Pregabalin is a synthetic amino acid compound effective in clinical trials for the treatment of post-herpetic neuralgia, diabetic peripheral neuropathy, generalized anxiety disorder and adjunctive therapy for partial seizures of epilepsy. However, the mechanisms by which pregabalin exerts its therapeutic effects are not yet completely understood. In vitro studies have shown that pregabalin binds with high affinity to the alpha(2)-delta (alpha(2)-delta) subunits (Type 1 and 2) of Voltage-Gated Calcium Channels. To assess whether alpha(2)-delta Type 1 is the major central nervous system (CNS) binding protein for pregabalin in vivo, a mutant mouse with an arginine-to-alanine mutation at amino acid 217 of the alpha(2)-delta Type 1 protein (R217A mutation) was generated. Previous site-directed mutagenesis studies revealed that the R217A mutation dramatically reduces alpha(2)-delta 1 binding to pregabalin in vitro. In this autoradiographic analysis of R217A mice, we show that the mutation to alpha(2)-delta Type 1 substantially reduces specific pregabalin binding in CNS regions that are known to preferentially express the alpha(2)-delta Type 1 protein, notably the neocortex, hippocampus, basolateral amygdala and spinal cord. In mutant mice, pregabalin binding was robust throughout regions where the alpha(2)-delta Type 2 subunit mRNA is abundant, such as cerebellum. These findings, in conjunction with prior in vitro binding data, provide evidence that the alpha(2)-delta Type 1 subunit of Voltage-Gated Calcium Channels is the major binding protein for pregabalin in CNS. Moreover, the distinct localization of alpha(2)-delta Type 1 and mutation-resistant binding (assumed to be alpha(2)-delta Type 2) in brain areas subserving different functions suggests that identification of subunit-specific ligands could further enhance pharmacologic specificity.
James Offord - One of the best experts on this subject based on the ideXlab platform.
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Calcium channel alpha2 delta type 1 subunit is the major binding protein for pregabalin in neocortex hippocampus amygdala and spinal cord an ex vivo autoradiographic study in alpha2 delta type 1 genetically modified mice
Brain Research, 2006Co-Authors: Feng Bian, Zheng Li, James Offord, Duff M Davis, Julie Mccormick, Charles Taylor, Lary C WalkerAbstract:Abstract Pregabalin is a synthetic amino acid compound effective in clinical trials for the treatment of post-herpetic neuralgia, diabetic peripheral neuropathy, generalized anxiety disorder and adjunctive therapy for partial seizures of epilepsy. However, the mechanisms by which pregabalin exerts its therapeutic effects are not yet completely understood. In vitro studies have shown that pregabalin binds with high affinity to the alpha2-delta (α2-δ) subunits (Type 1 and 2) of Voltage-Gated Calcium Channels. To assess whether α2-δ Type 1 is the major central nervous system (CNS) binding protein for pregabalin in vivo, a mutant mouse with an arginine-to-alanine mutation at amino acid 217 of the α2-δ Type 1 protein (R217A mutation) was generated. Previous site-directed mutagenesis studies revealed that the R217A mutation dramatically reduces α2-δ 1 binding to pregabalin in vitro. In this autoradiographic analysis of R217A mice, we show that the mutation to α2-δ Type 1 substantially reduces specific pregabalin binding in CNS regions that are known to preferentially express the α2-δ Type 1 protein, notably the neocortex, hippocampus, basolateral amygdala and spinal cord. In mutant mice, pregabalin binding was robust throughout regions where the α2-δ Type 2 subunit mRNA is abundant, such as cerebellum. These findings, in conjunction with prior in vitro binding data, provide evidence that the α2-δ Type 1 subunit of Voltage-Gated Calcium Channels is the major binding protein for pregabalin in CNS. Moreover, the distinct localization of α2-δ Type 1 and mutation-resistant binding (assumed to be α2-δ Type 2) in brain areas subserving different functions suggests that identification of subunit-specific ligands could further enhance pharmacologic specificity.
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Calcium channel alpha2 delta type 1 subunit is the major binding protein for pregabalin in neocortex hippocampus amygdala and spinal cord an ex vivo autoradiographic study in alpha2 delta type 1 genetically modified mice
Brain Research, 2006Co-Authors: Feng Bian, James Offord, Duff M Davis, Julie Mccormick, Charles Taylor, Lary C WalkerAbstract:Pregabalin is a synthetic amino acid compound effective in clinical trials for the treatment of post-herpetic neuralgia, diabetic peripheral neuropathy, generalized anxiety disorder and adjunctive therapy for partial seizures of epilepsy. However, the mechanisms by which pregabalin exerts its therapeutic effects are not yet completely understood. In vitro studies have shown that pregabalin binds with high affinity to the alpha(2)-delta (alpha(2)-delta) subunits (Type 1 and 2) of Voltage-Gated Calcium Channels. To assess whether alpha(2)-delta Type 1 is the major central nervous system (CNS) binding protein for pregabalin in vivo, a mutant mouse with an arginine-to-alanine mutation at amino acid 217 of the alpha(2)-delta Type 1 protein (R217A mutation) was generated. Previous site-directed mutagenesis studies revealed that the R217A mutation dramatically reduces alpha(2)-delta 1 binding to pregabalin in vitro. In this autoradiographic analysis of R217A mice, we show that the mutation to alpha(2)-delta Type 1 substantially reduces specific pregabalin binding in CNS regions that are known to preferentially express the alpha(2)-delta Type 1 protein, notably the neocortex, hippocampus, basolateral amygdala and spinal cord. In mutant mice, pregabalin binding was robust throughout regions where the alpha(2)-delta Type 2 subunit mRNA is abundant, such as cerebellum. These findings, in conjunction with prior in vitro binding data, provide evidence that the alpha(2)-delta Type 1 subunit of Voltage-Gated Calcium Channels is the major binding protein for pregabalin in CNS. Moreover, the distinct localization of alpha(2)-delta Type 1 and mutation-resistant binding (assumed to be alpha(2)-delta Type 2) in brain areas subserving different functions suggests that identification of subunit-specific ligands could further enhance pharmacologic specificity.
