“…Studies of RGS14 in mouse brain are valuable, but are limited in human translatability because RGS14 is expressed at different levels in certain brain regions in rodents relative to primates (Figures 2 and 3, and also see Figure 2 in Harbin et al, 2021); however note that RGS14 is one of the few proteins highly expressed in CA2 in both mice and humans (Evans et al, 2014; Lein et al, 2007; Squires, Gerber, et al, 2018). In addition, human RGS14 contains a C‐terminal PDZ motif that is not present in the rodent homolog that binds PDZ proteins in humans (Friedman et al, 2022). While differential expression patterns are more difficult to address, differences in RGS14 protein homology between primates and rodents could be addressed by performing studies on “humanized” mice manipulated to express human RGS14.…”
Section: Discussionmentioning
confidence: 99%
“…RGS14 protein expression has been reported in rodent brain, heart, lung, kidney, and spleen (Agudelo et al, 2018; Kardestuncer et al, 1998; Snow et al, 1997). While recent studies have identified roles for RGS14 in heart (Li et al, 2016), adipocytes (Vatner et al, 2018), and kidney (Friedman et al, 2022), most studies of RGS14 have centered on understanding its role in the brain. Within mouse brain, RGS14 is highly expressed in the hippocampus, most notably area CA2 (Figure 3).…”
Section: Rgs14 Regulation Of Synaptic Plasticity In Rodent Hippocampa...mentioning
confidence: 99%
“…Interestingly, RGS14 in human and non‐human primates (but not rodent) contain an extra C‐terminal 21 amino acids that code for a class I PDZ‐recognition sequence (PDZ motif) (Friedman et al, 2022). Recent studies in kidney show that the human RGS14‐PDZ motif binds the scaffolding protein NHERF1 in human kidney proximal tubule cells which, in turn, binds to the sodium phosphate cotransporter 2a (NPT2A) to mediate renal phosphate transport (Friedman et al, 2022). The presence of human RGS14 stabilizes the NPT2A:NHERF1 complex, acting as a regulator of parathyroid hormone (PTH) and FGF23‐sensitive phosphate transport (Friedman et al, 2022).…”
Section: Rgs14 Is a Multifunctional Signaling Protein That Integrates...mentioning
confidence: 99%
“…Recent studies in kidney show that the human RGS14‐PDZ motif binds the scaffolding protein NHERF1 in human kidney proximal tubule cells which, in turn, binds to the sodium phosphate cotransporter 2a (NPT2A) to mediate renal phosphate transport (Friedman et al, 2022). The presence of human RGS14 stabilizes the NPT2A:NHERF1 complex, acting as a regulator of parathyroid hormone (PTH) and FGF23‐sensitive phosphate transport (Friedman et al, 2022). Roles for RGS14‐PDZ binding partners in brain and specifically within CA2 hippocampal neurons remain an ongoing area of interest.…”
Section: Rgs14 Is a Multifunctional Signaling Protein That Integrates...mentioning
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.
“…Studies of RGS14 in mouse brain are valuable, but are limited in human translatability because RGS14 is expressed at different levels in certain brain regions in rodents relative to primates (Figures 2 and 3, and also see Figure 2 in Harbin et al, 2021); however note that RGS14 is one of the few proteins highly expressed in CA2 in both mice and humans (Evans et al, 2014; Lein et al, 2007; Squires, Gerber, et al, 2018). In addition, human RGS14 contains a C‐terminal PDZ motif that is not present in the rodent homolog that binds PDZ proteins in humans (Friedman et al, 2022). While differential expression patterns are more difficult to address, differences in RGS14 protein homology between primates and rodents could be addressed by performing studies on “humanized” mice manipulated to express human RGS14.…”
Section: Discussionmentioning
confidence: 99%
“…RGS14 protein expression has been reported in rodent brain, heart, lung, kidney, and spleen (Agudelo et al, 2018; Kardestuncer et al, 1998; Snow et al, 1997). While recent studies have identified roles for RGS14 in heart (Li et al, 2016), adipocytes (Vatner et al, 2018), and kidney (Friedman et al, 2022), most studies of RGS14 have centered on understanding its role in the brain. Within mouse brain, RGS14 is highly expressed in the hippocampus, most notably area CA2 (Figure 3).…”
Section: Rgs14 Regulation Of Synaptic Plasticity In Rodent Hippocampa...mentioning
confidence: 99%
“…Interestingly, RGS14 in human and non‐human primates (but not rodent) contain an extra C‐terminal 21 amino acids that code for a class I PDZ‐recognition sequence (PDZ motif) (Friedman et al, 2022). Recent studies in kidney show that the human RGS14‐PDZ motif binds the scaffolding protein NHERF1 in human kidney proximal tubule cells which, in turn, binds to the sodium phosphate cotransporter 2a (NPT2A) to mediate renal phosphate transport (Friedman et al, 2022). The presence of human RGS14 stabilizes the NPT2A:NHERF1 complex, acting as a regulator of parathyroid hormone (PTH) and FGF23‐sensitive phosphate transport (Friedman et al, 2022).…”
Section: Rgs14 Is a Multifunctional Signaling Protein That Integrates...mentioning
confidence: 99%
“…Recent studies in kidney show that the human RGS14‐PDZ motif binds the scaffolding protein NHERF1 in human kidney proximal tubule cells which, in turn, binds to the sodium phosphate cotransporter 2a (NPT2A) to mediate renal phosphate transport (Friedman et al, 2022). The presence of human RGS14 stabilizes the NPT2A:NHERF1 complex, acting as a regulator of parathyroid hormone (PTH) and FGF23‐sensitive phosphate transport (Friedman et al, 2022). Roles for RGS14‐PDZ binding partners in brain and specifically within CA2 hippocampal neurons remain an ongoing area of interest.…”
Section: Rgs14 Is a Multifunctional Signaling Protein That Integrates...mentioning
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.
“…To date, there have been at least 20 distinct RGS proteins classified, which play various regulatory roles and can be divided into seven families [ 14 ]: A/RZ family includes RGS17, RGS19 and RGS20; B/R4 family includes RGS1, RGS2, RGS3, RGS4, RGS5, RGS8, RGS13, RGS16, RGS18, RGS21; C/R7 family includes RGS6, RGS7, RGS9 and RGS11; D/R12 family includes RGS10, RGS12 and RGS14; E/RA family includes Axin and Axin2; F/GEF family includes P115-RhoGEF, GRK2 and RGS22; G/GRK family includes GRK1, GRK4, GRK5, GRK6 and GRK7. However, as some RGS proteins with a number of genetic variations continue to be revealed, the number of new RGS proteins discovered is still increasing, such as the RGS6 protein that possesses several splicing variants with varied functions and cellular localization [ 15 ], and the RGS14 protein with genetic variants that disrupt downstream signaling activation [ 16 ]. Fig.…”
As negative modulators of G-protein-coupled receptors (GPCRs) signaling, regulators of G protein signaling (RGS) proteins facilitate various downstream cellular signalings through regulating kinds of heterotrimeric G proteins by stimulating the guanosine triphosphatase (GTPase) activity of G-protein α (Gα) subunits. The expression of RGS proteins is dynamically and precisely mediated by several different mechanisms including epigenetic regulation, transcriptional regulation -and post-translational regulation. Emerging evidence has shown that RGS proteins act as important mediators in controlling essential cellular processes including cell proliferation, survival -and death via regulating downstream cellular signaling activities, indicating that RGS proteins are fundamentally involved in sustaining normal physiological functions and dysregulation of RGS proteins (such as aberrant expression of RGS proteins) is closely associated with pathologies of many diseases such as cancer. In this review, we summarize the molecular mechanisms governing the expression of RGS proteins, and further discuss the relationship of RGS proteins and cancer.
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