Transglutaminase in Receptor and Neurotransmitter-Regulated Functions

Abstract

Transglutaminases (TGs) and especially TG2 play important roles in neurotransmitter and receptor signaling pathways. Three different mechanisms by which TG2 interacts with neurotransmitter and receptor signaling systems will be discussed in this review. The first way in which TG2 interacts with receptor signaling is via its function as a guanine nucleotide binding protein (G-protein) coupling to G-protein coupled receptors (GPCRs) to activate down-stream signaling pathways. TG2 can exist in a least two conformations, a closed GTP-bound conformation and an open calcium-bound conformation. In the closed GTP-bound conformation, TG2 is capable of functioning as a G-protein for GPCRs. In the open calcium-bound conformation, TG2 catalyzes a transamidation reaction cross-linking proteins or catalyzing the covalent binding of a mono- or polyamine to a protein. The second mechanism is regulation of the transamidation reaction catalyzed by TG2 via receptor stimulation which can increase local calcium concentrations and thereby increase transamidation reactions. The third way in which TG2 plays a role in neurotransmitter and receptor signaling systems is via its use of monoamine neurotransmitters as a substrate. Monoamine neurotransmitters including serotonin can be substrates for transamidation to a protein often a small G-protein (also known as a small GTPase) resulting in activation of the small G-protein. The transamidation of a monoamine neurotransmitter or serotonin has been designated as monoaminylation or more specifically serotonylation, respectively. Other proteins are also targets for monoaminylation such as fibronectin and cytoskeletal proteins. These receptor and neurotransmitter-regulated reactions by TG2 play roles in physiological and key pathophysiological processes.

Keywords: Gαh; monoaminylation; serotonylation; transamidation; transglutaminase.

Fig. 1

TG2 in the closed conformation. In the closed conformation, TG2 functions as a G-protein capable of coupling to GPCRs and signaling through down-stream pathways including activation of PLCΔ1 to convert PIP2 to DAG and IP₃. IP₃ binds to IP₃ receptors on the ER leading to the release of Ca²⁺ from the ER. In the GTPbound form, TG2/Gαh dissociates from calreticulin/Gβh. Insert: TG2 adopts a closed conformation and binds GTP (small black circle) in the presence of low Ca²⁺ and high GTP concentrations. In higher concentrations of Ca²⁺, TG2 binds Ca²⁺ and adopts an open conformation. The four domains of TG2 are depicted as yellow, orange, pink and green ovals to represent the β-sandwich, catalytic core, β-barrel 1 and β-barrel 2 domains.

Fig. 2

TG2 in the open conformation. In the open conformation, TG2 catalyzes transamidation reactions. In human TG2, there are six binding sites for Ca²⁺ ions (small yellow circles) to bind to TG2 in the open conformation. These Ca²⁺ binding sites are highly conserved attesting to their importance ^[22]. Mutations within these binding sites can give rise to reduced transamidation activity and are found in patients with disorders in glucose metabolism ^[23]. The elevation of Ca²⁺ concentrations needed for the open conformation can occur at the cell membrane through two well defined neurotransmitter-dependent mechanisms. Ca²⁺ concentrations can be elevated at the cell membrane through neurotransmitter-gated ion channels (top right) or through Gαq/11-coupled GPCRs (upper left) activation of PLCβ and production of IP₃. Stimulation of IP₃ receptors on the ER results in release of Ca²⁺ (lower left). The TG2-catalyzed transamidation reaction can result in intermolecular cross-linked proteins, intramolecular cross-linked proteins or transamidation of poly- or monoamines to proteins such as monoaminylation of small G-proteins (GTPases). A third receptormediated mechanism to increase TG2 transamidation appears to involve the transport of extracellular Ca²⁺ into the cell but is less well understood and not shown here.