Facilitation of Long-Term Potentiation by Muscarinic M1 Receptors Is Mediated by Inhibition of SK Channels

Abstract

SummaryMuscarinic receptor activation facilitates the induction of synaptic plasticity and enhances cognitive function. However, the specific muscarinic receptor subtype involved and the critical intracellular signaling pathways engaged have remained controversial. Here, we show that the recently discovered highly selective allosteric M1 receptor agonist 77-LH-28-1 facilitates long-term potentiation (LTP) induced by theta burst stimulation at Schaffer collateral synapses in the hippocampus. Similarly, release of acetylcholine by stimulation of cholinergic fibers facilitates LTP via activation of M1 receptors. N-methyl-D-aspartate receptor (NMDAR) opening during theta burst stimulation was enhanced by M1 receptor activation, indicating this is the mechanism for LTP facilitation. M1 receptors were found to enhance NMDAR activation by inhibiting SK channels that otherwise act to hyperpolarize postsynaptic spines and inhibit NMDAR opening. Thus, we describe a mechanism where M1 receptor activation inhibits SK channels, allowing enhanced NMDAR activity and leading to a facilitation of LTP induction in the hippocampus.

Channel-anchored Protein Kinase CK2 and Protein Phosphatase 1 Reciprocally Regulate KCNQ2-containing M-channels via Phosphorylation of Calmodulin

“…Because TBB has been widely used in cellular experiments (14,16,17), we tested the effect of TBB on KCNQ2 current. TBB rapidly suppressed KCNQ2 current (Fig.…”

“…In contrast, the endothelial NO synthetase shows a reduced V max in the presence of phosphorylated CaM without changing its affinity for phosphorylated CaM (11). Regarding the effect of CaM phosphorylation on ion channels, detailed analysis has been described for the SK2 small conductance calcium-activated potassium channels (13,16,17). CK2 phosphomimetic CaM induces rightward shift of calciumdependent activation curve for SK2 channel, which leads to a reduced SK2 channel activity (13).…”

“…However, because protein kinase CK2 is constitutively active and phosphorylates a wide range of proteins (14,15), it has long been considered to be engaged in housekeeping functions (14). This traditional view has been revised by recent studies, where CK2-mediated phosphorylation of CaM was shown to play an active role in muscarinic facilitation of long term potentiation in the hippocampus by modulating SK2 channel activity (16,17).…”

Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

“…124 Furthermore, activation of M1 mAChRs by 77-LH-28-1 enhanced NMDA receptor activation in vitro, facilitating long-term potentiation. 125 Consistent with the interactions of AC-42, the mAChR orthosteric antagonists pirenzepine and scopolamine both produced a dextral displacement of the 77-LH-28-1 CRC; 124 however, 77-LH-28-1 has also been shown to compete with the prototypical muscarinic negative allosteric modulator C 7 /3-phth (at the NMS-occupied receptor), 115 adding weight to the theory that this scaffold interacts with portions of both orthosteric and allosteric sites on the M 1 mAChR.…”

Induction of Activity-Dependent LTD Requires Muscarinic Receptor Activation in Medial Prefrontal Cortex

“…Furthermore, mAChR activation facilitates (Kirkwood et al, 1999) or induces LTD in visual cortex (McCoy and McMahon, 2007) and induces LTD in perirhinal cortex (Massey et al, 2001). Activation of mAChRs can either increase (Markram and Segal, 1990;Harvey et al, 1993;Buchanan et al, 2010) or decrease (Jo et al, 2010) NMDA-mediated transmission, and this modulation of NMDARs may explain, at least in part, how mAChRs can affect synaptic plasticity.…”