Results: 3

1.
Figure 1

Figure 1. RSK2 phosphorylates 5-HT2A receptors to induce a ‘tonic brake’ on signaling. From: 5-HT2A SEROTONIN RECEPTOR BIOLOGY: Interacting proteins, kinases and paradoxical regulation.

Shown is our current understanding of the molecular details responsible for RSK2-mediated attenuation of 5-HT2A signaling. According to our current concepts, RSK2 tonically phosphorylates 5-HT2A receptors at a nonconserved serine residue in the i3 loop (S314) via growth-factor-mediated activation (Strachan et al, 2009a, 2009b; Strachan et al 2010).

Bryan L Roth. Neuropharmacology. ;61(3):348-354.
2.
Figure 3

Figure 3. Paradoxical regulation of 5-HT2A receptors. From: 5-HT2A SEROTONIN RECEPTOR BIOLOGY: Interacting proteins, kinases and paradoxical regulation.

Shown is our current understanding of the cellular mechanisms by which agonists and antagonists can induce receptor internalization and down-regulation. Both agonists and antagonists internalize 5-HT2A receptors via the endosome-clathrin coated pit pathway. Whether arrestins are crucial scaffolds for internalization is cell-type specific. Once receptors are internalized they may be recycled to the cell surface or, following chronic drug exposure, degraded via lysosomes and, perhaps, other pathways (e.g. ubiquitination).

Bryan L Roth. Neuropharmacology. ;61(3):348-354.
3.
Figure 2

Figure 2. 5-HT2A receptors and functional selectivity. From: 5-HT2A SEROTONIN RECEPTOR BIOLOGY: Interacting proteins, kinases and paradoxical regulation.

Shown are three-dimensional cartoons of three distinct receptor conformations stabilized by distinct agonists. As shown, drugs (both ‘agonists’ and ‘antagonists’) can stabilize distinct receptor conformations leading to biased interactions with various down-stream effectors. The down-stream effector pathways are indicated by arrows going from the three dimensional receptor cartoons. These effector pathways can include canonical (G-protein dependent) and non-canonical (arrestin-ergic, scaffolding protein –dependent) signaling. As is shown, two different canonical pathways are demonstrated on the right (PKC activation; Ca++ release) and left (kinase and channel activation) with arrestin-ergic signaling shown in the middle.

Bryan L Roth. Neuropharmacology. ;61(3):348-354.

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