Ketamine and Calcium Signaling-A Crosstalk for Neuronal Physiology and Pathology

Abstract

Ketamine is a non-competitive antagonist of NMDA (N-methyl-D-aspartate) receptor, which has been in clinical practice for over a half century. Despite recent data suggesting its harmful side effects, such as neuronal loss, synapse dysfunction or disturbed neural network formation, the drug is still applied in veterinary medicine and specialist anesthesia. Several lines of evidence indicate that structural and functional abnormalities in the nervous system caused by ketamine are crosslinked with the imbalanced activity of multiple Ca²⁺-regulated signaling pathways. Due to its ubiquitous nature, Ca²⁺ is also frequently located in the center of ketamine action, although the precise mechanisms underlying drug's negative or therapeutic properties remain mysterious for the large part. This review seeks to delineate the relationship between ketamine-triggered imbalance in Ca²⁺ homeostasis and functional consequences for downstream processes regulating key aspects of neuronal function.

Keywords: AMPA receptor; NMDA receptor; calcium; ketamine; mTOR signaling; neuronal function; signal transduction.

Figure 1

Schematic model of ketamine interaction with NMDA receptor. NMDA receptors are glutamatergic, ligand-gated ion channels comprising of four subunits forming a central pore that is permeable for Ca²⁺. Up to date, seven different subunits have been identified: GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B. However, NMDA receptor is typically composed of two GluN1 and two GluN2 subunits or a mixture of GluN2/GluN3 subunits. At resting state, the pore is occupied by Mg²⁺, but upon depolarization, the magnesium block is removed allowing Ca²⁺ to enter the cell. Besides depolarization, the activation of the receptor requires concurrent binding of L-glutamate and glycine/D-serine. Pore opening makes it accessible to ketamine which binds to PCP site and blocks further Ca²⁺ influx. The (S)-enantiomer of ketamine binds to the same site. In addition to ketamine and glutamate/glycine binding sites, several other known sites for regulation have been identified in NMDA receptor and they are reviewed in [2,3,5].

Figure 2

Calcium homeostasis and signaling in healthy neurons. Ca²⁺ can enter the cell during the “on” phase through voltage-dependent calcium channels (VDCCs), transient receptor potential channels (TRPCs), calcium release-activated calcium channel (ORAI1) or through glutamate-activated receptor-operated channels: N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate acid receptors (AMPARs). Calcium can be mobilized from the ER upon activation of some G protein-coupled receptors (GPCRs) via inositol-1,4,5-triphosphate (IP₃) receptors (IP₃Rs) or its release may occur through ryanodine receptors (RyRs). Depletion of the ER is followed by the activation of store-operated calcium entry (SOCE) which is based on the interaction between ORAI1 and the stromal interaction molecule 1 (STIM1). Intracellular Ca²⁺ increases are buffered by calcium-binding proteins but some Ca²⁺ signals can reach the nucleus and affect gene transcription. During the “off” phase, cytosolic Ca²⁺ is sequestered by sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA), secretory pathway Ca²⁺-ATPase (SPCA) or mitochondrial uniporter (MCU) to the ER, Golgi apparatus and mitochondria, respectively, or transported to the extracellular milieu by plasma membrane Ca²⁺-ATPase (PMCA) and Na⁺/Ca²⁺ exchanger (NCX). Ca²⁺ in the nucleus is controlled independently.

Figure 3

Schematic action of ketamine on mTOR pathway. Ketamine blockade of NMDARs on tonic firing GABA interneurons results in disinhibition of glutamate transmission causing a subsequent glutamate burst. This rapid glutamate burst activates AMPARs and leads to subsequent Ca²⁺ influx through L-type voltage-dependent Ca²⁺ channels (VDCCs). Ca²⁺ promotes BDNF release, which acts via Tropomyosin receptor kinase B/Protein kinase B (TrkB-Akt) to stimulate mTOR signalling. The different effects are linked with mTORC1 and mTORC2 activity. mTORC1, by phosphorylation, activates the ribosomal protein S6 kinase (S6K), as well as represses the inhibitory 4E binding proteins (4E-PB). This concert of events increases the translation of synaptic proteins (PSD95, synapsin-1, GluA1, GluA2) promoting synaptogenesis and intensifying translation of BDNF. Akt/PKB and PKC isoforms are the main substrates regulated by mTORC2. PKC-dependent phosphorylation of the growth-associated protein 43 (GAP43) and MARKS plays an important role in rearrangement of actin cytoskeleton and synaptic transmission. Close relation between GAP43 and calcium-binding protein - calmodulin (CaM) also affects several Ca²⁺/CaM-regulated neuronal processes. Additionally, AKT/PKB can phosphorylate the mTORC1 augmenting it activation.