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Activation of Phosphatidylinositol-Linked Dopamine Receptors Induces a Facilitation of Glutamate-Mediated Synaptic Transmission in the Lateral Entorhinal Cortex.

Glovaci I, Chapman CA - PLoS ONE (2015)

Bottom Line: However, the facilitation was blocked by blocking Ca2+ release from internal stores via inositol 1,4,5-trisphosphate (InsP3) receptors or ryanodine receptors.Follow-up studies demonstrated that inhibiting CaMKII activity with KN-93 failed to block the facilitation, but that application of the protein kinase C inhibitor PKC(19-36) completely blocked the dopamine-induced facilitation.These signaling pathways may collaborate to enhance sensory and mnemonic function in the entorhinal cortex during tonic release of dopamine.

View Article: PubMed Central - PubMed

Affiliation: Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montréal, Québec, Canada.

ABSTRACT
The lateral entorhinal cortex receives strong inputs from midbrain dopamine neurons that can modulate its sensory and mnemonic function. We have previously demonstrated that 1 µM dopamine facilitates synaptic transmission in layer II entorhinal cortex cells via activation of D1-like receptors, increased cAMP-PKA activity, and a resulting enhancement of AMPA-receptor mediated currents. The present study assessed the contribution of phosphatidylinositol (PI)-linked D1 receptors to the dopaminergic facilitation of transmission in layer II of the rat entorhinal cortex, and the involvement of phospholipase C activity and release of calcium from internal stores. Whole-cell patch-clamp recordings of glutamate-mediated evoked excitatory postsynaptic currents were obtained from pyramidal and fan cells. Activation of D1-like receptors using SKF38393, SKF83959, or 1 µM dopamine induced a reversible facilitation of EPSCs which was abolished by loading cells with either the phospholipase C inhibitor U-73122 or the Ca2+ chelator BAPTA. Neither the L-type voltage-gated Ca2+ channel blocker nifedipine, nor the L/N-type channel blocker cilnidipine, blocked the facilitation of synaptic currents. However, the facilitation was blocked by blocking Ca2+ release from internal stores via inositol 1,4,5-trisphosphate (InsP3) receptors or ryanodine receptors. Follow-up studies demonstrated that inhibiting CaMKII activity with KN-93 failed to block the facilitation, but that application of the protein kinase C inhibitor PKC(19-36) completely blocked the dopamine-induced facilitation. Overall, in addition to our previous report indicating a role for the cAMP-PKA pathway in dopamine-induced facilitation of synaptic transmission, we demonstrate here that the dopaminergic facilitation of synaptic responses in layer II entorhinal neurons also relies on a signaling cascade dependent on PI-linked D1 receptors, PLC, release of Ca2+ from internal stores, and PKC activation which is likely dependent upon both DAG and enhanced intracellular Ca2+. These signaling pathways may collaborate to enhance sensory and mnemonic function in the entorhinal cortex during tonic release of dopamine.

No MeSH data available.


Related in: MedlinePlus

Proposed signaling pathways that govern the dopaminergic facilitation of AMPA-mediated EPSCs.Classical D1-receptors are coupled to adenylyl cyclase (AC) via Gs/olf proteins, and we have shown previously that the dopamine-induced facilitation is dependent upon the activity of both protein kinase A (PKA) and protein phosphatase 1 (PP1) [20]. The PKA-mediated activation of inhibitor 1 (I-1) or of DARPP32 (dopamine and cyclic AMP regulated phosphoprotein 32) at thr34 may inhibit activity of protein phosphatase 1 (PP1) and thereby potentiate EPSCs by reducing the dephosphorylation of AMPA GluR1 receptor subunits at ser845. The present results indicate that activation of D1-receptors coupled to phospholipase C (PLC) via Gq proteins is also required for the facilitation of EPSCs. PLC leads to production of diacylglycerol (DAG) and InsP3 from PIP2. InsP3 triggers Ca2+ release from internal stores via InsP3 receptor (InsP3R) activation, and may also trigger Ca2+ induced Ca2+ release via ryanodine receptors (RyR). Both increased cytosolic Ca2+ and DAG can activate protein kinase C (PKC) that can enhance AMPA receptor function via phosphorylation at ser831.
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pone.0131948.g005: Proposed signaling pathways that govern the dopaminergic facilitation of AMPA-mediated EPSCs.Classical D1-receptors are coupled to adenylyl cyclase (AC) via Gs/olf proteins, and we have shown previously that the dopamine-induced facilitation is dependent upon the activity of both protein kinase A (PKA) and protein phosphatase 1 (PP1) [20]. The PKA-mediated activation of inhibitor 1 (I-1) or of DARPP32 (dopamine and cyclic AMP regulated phosphoprotein 32) at thr34 may inhibit activity of protein phosphatase 1 (PP1) and thereby potentiate EPSCs by reducing the dephosphorylation of AMPA GluR1 receptor subunits at ser845. The present results indicate that activation of D1-receptors coupled to phospholipase C (PLC) via Gq proteins is also required for the facilitation of EPSCs. PLC leads to production of diacylglycerol (DAG) and InsP3 from PIP2. InsP3 triggers Ca2+ release from internal stores via InsP3 receptor (InsP3R) activation, and may also trigger Ca2+ induced Ca2+ release via ryanodine receptors (RyR). Both increased cytosolic Ca2+ and DAG can activate protein kinase C (PKC) that can enhance AMPA receptor function via phosphorylation at ser831.

Mentions: It is well-acknowledged that activation of D1-like receptors linked to Gs/olf proteins can lead to increased glutamatergic transmission via increased activity in the cAMP-PKA pathway in other brain regions [24, 65] and we previously reported a similar PKA-dependent dopaminergic potentiation of AMPA currents in lateral entorhinal cortex slices [20]. In the present paper, we describe an additional intracellular pathway that depends on activation of PI-linked D1 receptors that are coupled to Gq proteins, which lead to increases in PLC activity, InsP3-dependent release of calcium from internal stores, and a PKC-dependent facilitation of glutamate-mediated synaptic responses (Fig 5). Full potentiation of glutamate transmission appears to require parallel activation of both PLC-dependent and PKA-dependent pathways, because activation of PI-linked D1-receptors alone produces a partial facilitation effect (Fig 2A1), and blocking signaling steps within either the PKA- or PLC-dependent signaling pathways blocks the full facilitation effect [20]. Although the role of SKF83959 as a selective PI-linked D1 receptor agonist has been recently questioned [66], our current findings demonstrate that the dopaminergic facilitation is dependent upon D1-receptors, PLC activity, Ca2+ signaling and PKC activity. These data point strongly to a role for PI-linked dopamine receptors and subsequent activation of the D1-PLC-Ca2+ signaling cascade. The involvement of both PKA- and PLC-dependent signaling cascades provides increased means through which other neuromodulators may gate synaptic transmission in lateral entorhinal cortex neurons, to either promote or restrict synaptic transmission.


Activation of Phosphatidylinositol-Linked Dopamine Receptors Induces a Facilitation of Glutamate-Mediated Synaptic Transmission in the Lateral Entorhinal Cortex.

Glovaci I, Chapman CA - PLoS ONE (2015)

Proposed signaling pathways that govern the dopaminergic facilitation of AMPA-mediated EPSCs.Classical D1-receptors are coupled to adenylyl cyclase (AC) via Gs/olf proteins, and we have shown previously that the dopamine-induced facilitation is dependent upon the activity of both protein kinase A (PKA) and protein phosphatase 1 (PP1) [20]. The PKA-mediated activation of inhibitor 1 (I-1) or of DARPP32 (dopamine and cyclic AMP regulated phosphoprotein 32) at thr34 may inhibit activity of protein phosphatase 1 (PP1) and thereby potentiate EPSCs by reducing the dephosphorylation of AMPA GluR1 receptor subunits at ser845. The present results indicate that activation of D1-receptors coupled to phospholipase C (PLC) via Gq proteins is also required for the facilitation of EPSCs. PLC leads to production of diacylglycerol (DAG) and InsP3 from PIP2. InsP3 triggers Ca2+ release from internal stores via InsP3 receptor (InsP3R) activation, and may also trigger Ca2+ induced Ca2+ release via ryanodine receptors (RyR). Both increased cytosolic Ca2+ and DAG can activate protein kinase C (PKC) that can enhance AMPA receptor function via phosphorylation at ser831.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4489908&req=5

pone.0131948.g005: Proposed signaling pathways that govern the dopaminergic facilitation of AMPA-mediated EPSCs.Classical D1-receptors are coupled to adenylyl cyclase (AC) via Gs/olf proteins, and we have shown previously that the dopamine-induced facilitation is dependent upon the activity of both protein kinase A (PKA) and protein phosphatase 1 (PP1) [20]. The PKA-mediated activation of inhibitor 1 (I-1) or of DARPP32 (dopamine and cyclic AMP regulated phosphoprotein 32) at thr34 may inhibit activity of protein phosphatase 1 (PP1) and thereby potentiate EPSCs by reducing the dephosphorylation of AMPA GluR1 receptor subunits at ser845. The present results indicate that activation of D1-receptors coupled to phospholipase C (PLC) via Gq proteins is also required for the facilitation of EPSCs. PLC leads to production of diacylglycerol (DAG) and InsP3 from PIP2. InsP3 triggers Ca2+ release from internal stores via InsP3 receptor (InsP3R) activation, and may also trigger Ca2+ induced Ca2+ release via ryanodine receptors (RyR). Both increased cytosolic Ca2+ and DAG can activate protein kinase C (PKC) that can enhance AMPA receptor function via phosphorylation at ser831.
Mentions: It is well-acknowledged that activation of D1-like receptors linked to Gs/olf proteins can lead to increased glutamatergic transmission via increased activity in the cAMP-PKA pathway in other brain regions [24, 65] and we previously reported a similar PKA-dependent dopaminergic potentiation of AMPA currents in lateral entorhinal cortex slices [20]. In the present paper, we describe an additional intracellular pathway that depends on activation of PI-linked D1 receptors that are coupled to Gq proteins, which lead to increases in PLC activity, InsP3-dependent release of calcium from internal stores, and a PKC-dependent facilitation of glutamate-mediated synaptic responses (Fig 5). Full potentiation of glutamate transmission appears to require parallel activation of both PLC-dependent and PKA-dependent pathways, because activation of PI-linked D1-receptors alone produces a partial facilitation effect (Fig 2A1), and blocking signaling steps within either the PKA- or PLC-dependent signaling pathways blocks the full facilitation effect [20]. Although the role of SKF83959 as a selective PI-linked D1 receptor agonist has been recently questioned [66], our current findings demonstrate that the dopaminergic facilitation is dependent upon D1-receptors, PLC activity, Ca2+ signaling and PKC activity. These data point strongly to a role for PI-linked dopamine receptors and subsequent activation of the D1-PLC-Ca2+ signaling cascade. The involvement of both PKA- and PLC-dependent signaling cascades provides increased means through which other neuromodulators may gate synaptic transmission in lateral entorhinal cortex neurons, to either promote or restrict synaptic transmission.

Bottom Line: However, the facilitation was blocked by blocking Ca2+ release from internal stores via inositol 1,4,5-trisphosphate (InsP3) receptors or ryanodine receptors.Follow-up studies demonstrated that inhibiting CaMKII activity with KN-93 failed to block the facilitation, but that application of the protein kinase C inhibitor PKC(19-36) completely blocked the dopamine-induced facilitation.These signaling pathways may collaborate to enhance sensory and mnemonic function in the entorhinal cortex during tonic release of dopamine.

View Article: PubMed Central - PubMed

Affiliation: Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montréal, Québec, Canada.

ABSTRACT
The lateral entorhinal cortex receives strong inputs from midbrain dopamine neurons that can modulate its sensory and mnemonic function. We have previously demonstrated that 1 µM dopamine facilitates synaptic transmission in layer II entorhinal cortex cells via activation of D1-like receptors, increased cAMP-PKA activity, and a resulting enhancement of AMPA-receptor mediated currents. The present study assessed the contribution of phosphatidylinositol (PI)-linked D1 receptors to the dopaminergic facilitation of transmission in layer II of the rat entorhinal cortex, and the involvement of phospholipase C activity and release of calcium from internal stores. Whole-cell patch-clamp recordings of glutamate-mediated evoked excitatory postsynaptic currents were obtained from pyramidal and fan cells. Activation of D1-like receptors using SKF38393, SKF83959, or 1 µM dopamine induced a reversible facilitation of EPSCs which was abolished by loading cells with either the phospholipase C inhibitor U-73122 or the Ca2+ chelator BAPTA. Neither the L-type voltage-gated Ca2+ channel blocker nifedipine, nor the L/N-type channel blocker cilnidipine, blocked the facilitation of synaptic currents. However, the facilitation was blocked by blocking Ca2+ release from internal stores via inositol 1,4,5-trisphosphate (InsP3) receptors or ryanodine receptors. Follow-up studies demonstrated that inhibiting CaMKII activity with KN-93 failed to block the facilitation, but that application of the protein kinase C inhibitor PKC(19-36) completely blocked the dopamine-induced facilitation. Overall, in addition to our previous report indicating a role for the cAMP-PKA pathway in dopamine-induced facilitation of synaptic transmission, we demonstrate here that the dopaminergic facilitation of synaptic responses in layer II entorhinal neurons also relies on a signaling cascade dependent on PI-linked D1 receptors, PLC, release of Ca2+ from internal stores, and PKC activation which is likely dependent upon both DAG and enhanced intracellular Ca2+. These signaling pathways may collaborate to enhance sensory and mnemonic function in the entorhinal cortex during tonic release of dopamine.

No MeSH data available.


Related in: MedlinePlus