Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

Abstract

G-protein-coupled receptors (GPCRs) play critical roles in regulating brain function. Recent advances have greatly expanded our understanding of these receptors as complex signaling machines that can adopt numerous conformations and modulate multiple downstream signaling pathways. While agonists and antagonists have traditionally been pursued to target GPCRs, allosteric modulators provide several mechanistic advantages, including the ability to distinguish between closely related receptor subtypes. Recently, the discovery of allosteric ligands that confer bias and modulate some, but not all, of a given receptor's downstream signaling pathways can provide pharmacological modulation of brain circuitry with remarkable precision. In addition, allosteric modulators with unprecedented specificity have been developed that can differentiate between subpopulations of a given receptor subtype based on the receptor's dimerization state. These advances are not only providing insight into the biological roles of specific receptor populations, but hold great promise for treating numerous CNS disorders.

Keywords: GPCR; NAM; PAM; allosteric modulator; dopamine receptor; mAChR; mGlu; metabotropic glutamate receptor; muscarinic receptor; schizophrenia.

Figure 1. Positive allosteric modulators modulate receptor activity while maintaining spatial and temporal dynamics associated with neurotransmitter release

Communication between neurons is commonly encoded by neurotransmitter release events emanating from presynaptic terminals resulting in postsynaptic receptor activation (A). Presynaptic activity patterns (B), and the proximity of a receptor from a neurotransmitter release site, both play a key role in determining postsynaptic receptor activity patterns. In receptor populations that are present in the synaptic cleft, the site of neurotransmitter release is sufficiently proximal to the receptor such that each release event may induce receptor activation (C). Receptor populations that are expressed in extrasynaptic or perisynaptic areas, which are further removed from neurotransmitter release sites, may not be exposed to sufficient neurotransmitter levels following a single release event to become active. However these receptors may be activated following bursts of high-frequency activity when neurotransmitter levels are sufficiently elevated to spill out from the synapse (D). Exogenously applied agonists activate receptors with a temporal profile (E) that is very different from presynaptic activity patterns (B) and will activate receptors regardless of their proximity to presynaptic inputs. In the simplest case, positive allosteric modulators (PAMs) of post-synaptic receptors do not affect presynaptic firing rates (F), but potentiate responses to the endogenous neurotransmitter while maintaining temporally and spatially coded information with respect to receptor activity patterns (G and H). This activity-dependence of allosteric modulators can avoid detrimental effects due to excessive receptor activation and preserve complex physiology such as spike-timing dependent plasticity.

Figure 2. Ability of allosteric modulators to confer bias of GPCR signaling

GPCRs can adopt multiple conformations upon neurotransmitter binding that can lead to activation of numerous signaling pathways (A). Non-biased allosteric modulators equally potentiate (B) or inhibit (C) all the signaling pathways that are activated by an agonist. However, some PAMs and NAMs can confer bias to GPCR signaling and selectively modulate coupling of GPCRs to specific signaling pathways while having little or no effect on others (D and E). These tools are affording the opportunity to determine the outcome of modulating a specific receptor-mediated signaling pathway, and hold great therapeutic potential by allowing receptor activation to be steered in maximally beneficial directions.

Figure 3. Allosteric modulators can differentially modulate receptor populations based on their dimerization

Many GPCRs can form oligomers either as homodimers (containing two receptors of the same subtype) or heterodimers (containing two different receptor subtypes). As depicted above using mGlu₄ and mGlu₂ receptors as an example, some PAMs (such as VU0155041) are active at both mGlu₄/mGlu₄ homodimer and mGlu₄/mGlu₂ heterodimer complexes (A; Potentiation of receptor activity is depicted by orange shading). Other PAMs (such as PHCCC) selectively activate mGlu₄ homodimers but are inactive at mGlu₄/mGlu₂ heterodimers (B). Furthermore, while no examples have been described to date, it is possible that other classes of PAMs could be active at the heterodimer, but inactive at the homodimer (C). These novel tools that can distinguish between receptor complexes will shed light onto the physiological significance of homodimer and heterodimer complexes and could provide therapeutic benefits through incredibly precise modulation of circuitry that targets not only a given receptor subtype, but can target specific receptor complexes.

Figure 4. The potential therapeutic benefits of selectively regulating dopaminergic signaling in the basal ganglia

Midbrain dopamine (DA) neurons project to several nuclei including the striatum, nucleus accumbens (NAcc), prefrontal cortex (PFC), cortex, and hippocampus. DA signaling is dysregulated in schizophrenia manifesting in excessive DA release in the striatum and NAcc that is associated with the positive symptoms such as hallucinations and delusions (depicted as green shaded areas). However, DA signaling is not hyperactive in all brain regions and hypoactive disruptions in cortical and hippocampal DA signaling are thought to contribute to the negative symptoms such as anhedonia as well as the cognitive deficits. Currently available antipsychotics act by blocking DA D₂ receptors across all brain regions, including the areas that are already DA deficient, potentially worsening negative and cognitive symptoms (A). By depressing DA release through the release of local messengers in the hyperactive limbic brain regions, M₄ PAMs have the potential to correct hyperactive DA signaling without further depressing DA signaling in other areas (B), demonstrating how circuit-selective therapeutics have the potential to provide efficacy with reduced adverse effect liability.