The impact of receptor–receptor interactions in heteroreceptor complexes on brain plasticity

Abstract

Allosteric mechanisms in receptor heteromers markedly increase the repertoire of receptor recognition and signaling. Of high importance is the altered function in the receptor heteromer versus the receptor homomer. Such a change in receptor function is mainly brought about by agonist induced allosteric receptor–receptor interactions and leads to functional and structural plasticity. Receptor–receptor interactions integrating synaptic and volume transmission signals participate in a significant way in modulating bidirectional synaptic plasticity and thus Hebbian plasticity. One molecular mechanism that can contribute to a change of synaptic weight may be represented by multiple interactions between plasma membrane receptors forming higher order heteroreceptor complexes via oligomerization at the pre- and post-junctional level. Such long-lived heteroreceptor complexes may play a significant role in learning and memory.

Keywords::

• allosteric receptor–receptor interaction
• G protein-coupled receptor
• learning
• long term depression
• long term potentiation
• memory plasticity
• receptor heteromer
• receptor tyrosine kinase
• striatum

In the 1980s, neuropeptides were found to modulate the binding characteristics, especially the affinity, of the central monoamine receptors in membrane preparations in a receptor subtype specific way [1]. Thus, intramembrane receptor–receptor interactions did exist in addition to indirect actions via phosphorylation and changes in membrane potential. As a logical consequence for the indications of direct physical interactions between neuropeptide and monoamine receptors in the plasma membrane, the term heteromerization was introduced by us in 1993 to describe a specific interaction between different types of G protein-coupled receptors [2]. This can sometimes involve an adapter protein and sometimes require the assistance of scaffolding proteins to allow their interaction to occur. Allosteric mechanisms make possible the integrative activity taking place intermolecularly in receptor heteromers between the two protomers. A ‘guide-and-clasp’ manner for receptor–receptor interactions in the interface is proposed where ‘adhesive guides’ may be amino acid triplet homologies [3]. The allosteric mechanisms in receptor heteromers make possible a marked rise of the repertoire of G protein-coupled receptor recognition and signaling. Of high importance is the altered function in the receptor heteromer versus the receptor homomer through inter alia a change in its G protein selectivity, and thus in its signaling cascades and switching from G protein to β-arrestin2-mediated signaling [4,5]. Such a change in function is mainly brought about by agonist-induced allosteric receptor–receptor interactions and leads to functional plasticity, for example, in neurons and astrocytes [6].

The link of receptor–receptor interactions to neuronal plasticity was first discussed in 1993 [2]. The co-occurrence of several events and/or signals appears necessary for a long-lasting change in neuronal function which is true for the plastic phenomenon of long-term potentiation (LTP) and long-term depression (LTD) [7]. Intramembrane receptor–receptor interactions are coincidence detectors and therefore likely candidates for these types of neuroplasticity.

An example of the LTD phenomenon is the D2 receptor (D2R)-promoted LTD in the striato-pallidal GABA neurons [7]. It is of interest that mGluR5 blockade counteracts LTD in these neurons in spite of the fact this receptor appears to antagonize D2R protomer signaling through inhibitory receptor–receptor interactions in an extrasynaptic A2A–D2-mGluR5 heteroreceptor complex outside the glutamate synapse [8]. Thus, in this case, LTD is blocked by the need for mGluR5 signaling to increase the formation and release of endocannabinoids to reach via extrasynaptic volume transmission (VT) [9] the CB1 receptors on the glutamate nerve terminals which inhibit glutamate release [7]. It demonstrates the demand for CB1-mediated endocannabinoid VT on glutamate nerve terminals for D2R-induced LTD in the glutamate synapses on the striato-pallidal GABA neurons.

A spike-timing-dependent plasticity is present in these cortico-striatal synapses, and when postsynaptic spiking precedes presynaptic activity, LTD is produced. Instead, the reverse order leads to LTP [7]. In the presence of the D2R-like agonist quinpirole, however, the latter protocol with presynaptic activity preceding postsynaptic spiking did not cause LTP but LTD. It shows the powerful action of D2Rs in counteracting the neurochemical mechanisms, leading to LTP and switching it to LTD. D2R activation gives a downstate of the striato-pallidal GABA neurons through multiple actions at the striato-pallidal glutamate synapses [10] including antagonistic postsynaptic D2R-NMDA receptor–receptor interactions in heteroreceptor complexes [11,12] and inhibitory D2-A2A receptor–receptor interactions in extrasynaptic heteroreceptor complexes and at the adenylate cyclase level [4,13]. It is of substantial interest that the adenosine A2A receptors (A2AR) agonist CGS21680 when given together with quinpirole restored LTP on this glutamate synapse [7]. The mechanism is likely the antagonistic A2A-D2 receptor–receptor interaction in the extrasynaptic A2A–D2 heteroreceptor complex reducing the D2R protomer signaling [4,14]. Thus, these findings by the Surmeier group [7] strongly support the important role of receptor–receptor interactions of heteroreceptor complexes in modulating neuroplasticity. By bringing down extrasynaptic D2R protomer signaling and its inhibitory impact in addition to increasing A2AR signaling, neuroplasticity can switch from LTD to LTP. In line with this view, the A2AR antagonist SCH 58261 blocked the development of LTP in the D2R-rich striato-pallidal GABA neurons [7]. Thus, the excitatory influence of A2AR activation and its removal of the inhibitory post-junctional signaling of the D2R protomers in the A2A–D2 heteroreceptor complex is necessary for the LTP to develop in these glutamate synapses which also depends on NMDA receptor signaling. In Parkinson’s disease models with low striatal levels of dopamine, both spike-timing-dependent protocols induced LTP in the D2R-rich striato-pallidal GABA neurons demonstrating a change of plasticity in the Parkinson’s disease model related to a lack of a D2R tone [7]. Again, the A2AR activity played a relevant role since LTP was blocked by the A2AR antagonist. In this case, the mechanism should not involve the A2A–D2 heteroreceptor complex since the D2R protomer signaling is already markedly reduced but could involve facilitatory receptor interactions with α7 nicotinic receptors [15] in addition to A2AR homomer signaling over the AC-PKA cascade post-junctionally and increased release of glutamate prejunctionally [13,16]. The ligand for the A2AR is adenosine which is a VT modulator originating from ATP released from astroglia and glutamate terminals which is metabolized to adenosine from ATP via extracellular enzymes. These results therefore again demonstrate that VT signals play a relevant role in modulating LTP and LTD in the striato-pallidal GABA neurons. Thus, both receptor–receptor interactions and extrasynaptic VT participate in a significant way in modulating bidirectional synaptic plasticity and thus Hebbian plasticity which is linked to a precise coordination of presynaptic and postsynaptic activities.

A possible role of intramembrane receptor–receptor interactions in learning and memory was proposed via the formation of long-lived heteroreceptor complexes [17]. Learning in neuronal networks may occur by instructions to the neurons to change their synaptic weights (i.e., efficacies). One molecular mechanism that can contribute to a change of synaptic weight may be represented by multiple interactions between plasma membrane receptors forming receptor assemblies (higher-order heteroreceptor complexes, receptor mosaics) via oligomerization at the pre- and post-junctional level. These assemblies of receptors together with inter alia adapter proteins, G-proteins and ion channels form the plasma membrane-bound part of a complex molecular circuit, the cytoplasmic part of which consists especially of protein kinases, protein phosphatases and phosphoproteins. This molecular circuit has the capability to learn and store information. Engram formation will depend on the resetting of molecular circuits via the formation of new heteroreceptor complexes capable via receptor–receptor interactions of addressing the transduction of the chemical messages impinging on the cell membrane to certain sets of G-proteins, ion channels and other protein effectors. Short-term memory may occur by a transient stabilization of the receptor mosaics producing the appropriate change in the synaptic weight. Engram consolidation (long-term memory) may involve intracellular signals that translocate to the nucleus to cause the activation of immediate early genes and subsequent formation of postulated adapter proteins which stabilize the receptor mosaics with the formation of long-lived heteroreceptor complexes (receptor mosaics). The receptor mosaic hypothesis of the engram formation [17] was formulated in agreement with the Hebbian rule and gives a novel molecular basis for it by postulating that the presynaptic activity change in transmitter and modulator release reorganizes the receptor mosaics at postsynaptic level and subsequently at presynaptic level. This results in the formation of novel molecular circuits leading to a different integration of chemical signals impinging on pre- and postsynaptic membranes, which leads to a new value of the synaptic weight. Thus, long-lived heteroreceptor complexes of high order may play a significant role in learning and memory.

The resulting changes in extracellular signal-regulated kinases signaling may be of special relevance for long-term memory in view of its role in activity-dependent modifications of histone and thus in epigenetic processes [18]. Transcriptional and epigenetic regulation appears to participate in both Hebbian and non-Hebbian forms of plasticity [19], which may drive learning and memory at the molecular level through the formation and stabilization of molecular circuits with newly formed higher-order heteroreceptor complexes. This molecular plasticity change, whether transient or long term, can then alter the patterns of outflow in the brain circuits and induce transient and long-term changes in behaviors and cognitive functions. Of special relevance for structural plasticity, for example, in the dendritic tree and its spines, is the recruitment of receptor tyrosine kinase to the novel heteroreceptor complex, which may result, for example, in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary neuronal cultures [20,21]. It has also been demonstrated that A2ARs can recruit TrkB receptors to lipid rafts [22,23], which may involve receptor heteromerization processes.

Financial & competing interests disclosure

This work has been supported by the Swedish Medical Research Council (65X-715) to K Fuxe and by Karolinska Institutets Forskningsstiftelser 2013 to D.O.B-E. D.O.B-E belong to the ‘Academia de Biólogos Cubanos’. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.