RGS14 expression in CA2 hippocampus, amygdala, and basal ganglia: Implications for human brain physiology and disease

Abstract

RGS14 is a multifunctional scaffolding protein that is highly expressed within postsynaptic spines of pyramidal neurons in hippocampal area CA2. Known roles of RGS14 in CA2 include regulating G protein, H-Ras/ERK, and calcium signaling pathways to serve as a natural suppressor of synaptic plasticity and postsynaptic signaling. RGS14 also shows marked postsynaptic expression in major structures of the limbic system and basal ganglia, including the amygdala and both the ventral and dorsal subdivisions of the striatum. In this review, we discuss the signaling functions of RGS14 and its role in postsynaptic strength (long-term potentiation) and spine structural plasticity in CA2 hippocampal neurons, and how RGS14 suppression of plasticity impacts linked behaviors such as spatial learning, object memory, and fear conditioning. We also review RGS14 expression in the limbic system and basal ganglia and speculate on its possible roles in regulating plasticity in these regions, with a focus on behaviors related to emotion and motivation. Finally, we explore the functional implications of RGS14 in various brain circuits and speculate on its possible roles in certain disease states such as hippocampal seizures, addiction, and anxiety disorders.

Keywords: RGS proteins; RGS14; amygdala; basal ganglia; hippocampus; limbic system; striatum; synaptic plasticity.

Figure 1:. RGS14 binding partners and regulation of postsynaptic plasticity.

Human RGS14 (566 amino acids, ~63 KDa) is a multi-domain scaffolding protein that is highly expressed in postsynaptic dendritic spines of pyramidal neurons in hippocampal area CA2. The protein contains an RGS domain that binds non-selectively to active GTP-bound Gαi and Gαo isoforms to serve as a GTPase activating protein (GAP). RGS14 also contains tandem Ras-binding domains (R1 and R2). R1 binds active GTP-bound H-Ras and Rap2. RGS14 also bind Raf kinases (Raf1 and B-Raf). RGS14 is unusual in that it contains a GPR motif that selectively binds a second Gα subunit, specifically inactive GDP-bound Gαi1 or Gαi3, which anchor the protein complex at the plasma membrane. Human RGS14 also contains a C-terminal PDZ binding motif (-DSAL) that binds the PDZ protein NHERF1. RGS14 is phosphorylated at Ser218 which allows binding of 14-3-3γ to stabilize the protein complex in the cytosol. RGS14 is a nucleocytoplasmic shuttling protein that contains a nuclear localization sequence (NLS) and a nuclear export sequence (NES), the latter of which binds exportin (XPO1). RGS14 also binds activate calcium calmodulin (Ca²⁺/CaM) and Ca²⁺/CaM-Kinase-II (CaMKII), though the exact binding sites for these proteins are undefined. This image was created with BioRender.com

Figure 2:. RGS14 protein expression pattern in primate brain.

Images are presented rostral/front (A) to caudal/back (D). RGS14 is expressed in structures of the basal ganglia including the striatal (red) regions comprised of the caudate nucleus (Cau), putamen (Put) (A-D), and nucleus accumbens (NAc) (A), and also the non-striatal basal ganglia (yellow) regions that are the external globus pallidus (GPe) and internal globus pallidus (GPi) as well as the substantia nigra pars reticulata (SNr) (C-D). RGS14 also is found in structures of the limbic system: the olfactory areas (brown) including the entorhinal cortex (EC) (A-D), anterior olfactory nucleus (AON), (A) and piriform cortex (Pir) (B), amygdala (purple) regions including the basolateral amygdala (BLA) (C) and central amygdala (CeA), and in hippocampal (cyan) areas CA1 and CA2 (D).

Figure 3:. RGS14 protein expression pattern in mouse brain.

Images are presented rostral/front (A) to caudal/back (D). At the most rostral end of mouse brain (A), RGS14 is expressed in olfactory areas (brown) including the orbitofrontal cortex (OFC) and anterior olfactory nucleus (AON) and, moving more caudal, also in the piriform cortex (Pir) (B-C) and entorhinal cortex (D). RGS14 is expressed in rodent striatal (red) structures of the basal ganglia including the caudoputamen (CPu) and the nucleus accumbens (Nac) (B and C). Non-striatal basal ganglia structures where RGS14 is found (yellow) include the external globus pallidus (Gpe) and internal globus pallidus (Gpi) (C) as well as the substantia nigra (SNr) (C and D). in rodent brain, RGS14 is most highly expressed in limbic structures including hippocampal (cyan) area CA2 (C and D) and, to a lesser extent, the central amygdala (purple, CeA) (D).

Figure 4:. Major neurocircuits affected by RGS14.

Thick box borders indicate RGS14-expressing regions. Behavior is driven by a complex signaling flow between regions including the cortex, limbic system, basal ganglia, thalamus, and hypothalamus. See text for detailed descriptions. As a general overview, external information is first processed cortically (including olfactory cortex), then flows to the limbic system for emotional interpretation, then to the basal ganglia for processing of motivation and physical movement, then to the thalamus and back to the cortex for behavioral execution or inhibition. Limbic regions are also highly interconnected with the hypothalamus, which drives the physiological stress response. RGS14 may affect the synaptic strength of these connections at several points throughout the limbic system and basal ganglia. Abbreviations: AON = anterior olfactory nucleus, BLA = basolateral amygdala, BNST = bed nucleus of the stria terminalis, CeA = central amygdala, CPu = caudoputamen (rodents) or caudate and putamen (primates), EC = entorhinal cortex, HYPO = hypothalamus, NAc = nucleus accumbens, OFC = orbitofrontal cortex, Pir = piriform cortex, SNr = substantial nigra pars reticulata.