Abstract
The modulation of high-threshold Ca2+ currents by the selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), was investigated in cultured hippocampal neurons using whole-cell voltage-clamp recording. ACPD reduced high-threshold Ca2+ currents carried by Ba2+ with an EC50 of 15.5 μM. The inhibition was reversible, voltage dependent, and blocked by L-2-amino-3-phosphonopropionic acid (1 mM) or by pretreatment with pertussis toxin. Inhibition by ACPD was greatly enhanced, and became irreversible, when the nonhydrolyzable GTP analog GTP-γS was included in the whole-cell pipette. In some neurons, the Ba2+ current was inhibited by L(+)-2-amino-4-phosphonobutanoic acid (L-AP4) as well as ACPD while most cells were insensitive to L-AP4, suggesting that these agonists activate distinct receptors. The inhibition of Ca2+ currents was reduced but not eliminated in the presence of either ω-conotoxin GVIA or nifedipine, suggesting that both N- and L-type Ca2+ currents were affected. The degree and kinetics of inhibition were dependent on intracellular calcium. With [Ca]i <1 nM, inhibition had a fast onset (t ≈ 1-2 sec) and a rapid recovery, consistent with a membrane-delimited pathway. However, a slow component of inhibition appeared when the steady state [Ca]i was increased to 100 nM (t on set ≈ 3 min). The slow component did not require transient Ca2+ influx or release of intracellular Ca2+. We suggest that Ca2+ channel modulation by ACPD involves either two mGluR subtypes with separate coupling mechanisms or a single mGluR that couples to both mechanisms.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3041-3050 |
| Number of pages | 10 |
| Journal | Journal of Neuroscience |
| Volume | 13 |
| Issue number | 7 |
| State | Published - 1993 |
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Keywords
- Calcium channels
- G-proteins
- Hippocampus
- L-2-amino-4-phosphonobutanoic acid
- Metabotropic glutamate receptors
- Trans-ACPD
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
Modulation of calcium currents by a metabotropic glutamate receptor involves fast and slow kinetic components in cultured hippocampal neurons. / Sahara, Yoshinori; Westbrook, Gary.
In: Journal of Neuroscience, Vol. 13, No. 7, 1993, p. 3041-3050.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Modulation of calcium currents by a metabotropic glutamate receptor involves fast and slow kinetic components in cultured hippocampal neurons
AU - Sahara, Yoshinori
AU - Westbrook, Gary
PY - 1993
Y1 - 1993
N2 - The modulation of high-threshold Ca2+ currents by the selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), was investigated in cultured hippocampal neurons using whole-cell voltage-clamp recording. ACPD reduced high-threshold Ca2+ currents carried by Ba2+ with an EC50 of 15.5 μM. The inhibition was reversible, voltage dependent, and blocked by L-2-amino-3-phosphonopropionic acid (1 mM) or by pretreatment with pertussis toxin. Inhibition by ACPD was greatly enhanced, and became irreversible, when the nonhydrolyzable GTP analog GTP-γS was included in the whole-cell pipette. In some neurons, the Ba2+ current was inhibited by L(+)-2-amino-4-phosphonobutanoic acid (L-AP4) as well as ACPD while most cells were insensitive to L-AP4, suggesting that these agonists activate distinct receptors. The inhibition of Ca2+ currents was reduced but not eliminated in the presence of either ω-conotoxin GVIA or nifedipine, suggesting that both N- and L-type Ca2+ currents were affected. The degree and kinetics of inhibition were dependent on intracellular calcium. With [Ca]i <1 nM, inhibition had a fast onset (t ≈ 1-2 sec) and a rapid recovery, consistent with a membrane-delimited pathway. However, a slow component of inhibition appeared when the steady state [Ca]i was increased to 100 nM (t on set ≈ 3 min). The slow component did not require transient Ca2+ influx or release of intracellular Ca2+. We suggest that Ca2+ channel modulation by ACPD involves either two mGluR subtypes with separate coupling mechanisms or a single mGluR that couples to both mechanisms.
AB - The modulation of high-threshold Ca2+ currents by the selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), was investigated in cultured hippocampal neurons using whole-cell voltage-clamp recording. ACPD reduced high-threshold Ca2+ currents carried by Ba2+ with an EC50 of 15.5 μM. The inhibition was reversible, voltage dependent, and blocked by L-2-amino-3-phosphonopropionic acid (1 mM) or by pretreatment with pertussis toxin. Inhibition by ACPD was greatly enhanced, and became irreversible, when the nonhydrolyzable GTP analog GTP-γS was included in the whole-cell pipette. In some neurons, the Ba2+ current was inhibited by L(+)-2-amino-4-phosphonobutanoic acid (L-AP4) as well as ACPD while most cells were insensitive to L-AP4, suggesting that these agonists activate distinct receptors. The inhibition of Ca2+ currents was reduced but not eliminated in the presence of either ω-conotoxin GVIA or nifedipine, suggesting that both N- and L-type Ca2+ currents were affected. The degree and kinetics of inhibition were dependent on intracellular calcium. With [Ca]i <1 nM, inhibition had a fast onset (t ≈ 1-2 sec) and a rapid recovery, consistent with a membrane-delimited pathway. However, a slow component of inhibition appeared when the steady state [Ca]i was increased to 100 nM (t on set ≈ 3 min). The slow component did not require transient Ca2+ influx or release of intracellular Ca2+. We suggest that Ca2+ channel modulation by ACPD involves either two mGluR subtypes with separate coupling mechanisms or a single mGluR that couples to both mechanisms.
KW - Calcium channels
KW - G-proteins
KW - Hippocampus
KW - L-2-amino-4-phosphonobutanoic acid
KW - Metabotropic glutamate receptors
KW - Trans-ACPD
UR - http://www.scopus.com/inward/record.url?scp=0027231466&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0027231466&partnerID=8YFLogxK
M3 - Article
C2 - 8392538
AN - SCOPUS:0027231466
VL - 13
SP - 3041
EP - 3050
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 7
ER -