Receptor-receptor interactions as an integrative mechanism in nerve cells

Abstract

Several lines of evidence indicate that interactions among transmission lines can take place at the level of the cell membrane via interactions among macromolecules, integral or associated to the cell membrane, involved in signal recognition and transduction. The present view will focus on this last subject, i.e., on the interactions between receptors for chemical signals at the level of the neuronal membrane (receptor-receptor interaction). By receptor-receptor interaction we mean that a neurotransmitter or modulator, by binding to its receptor, modifies the characteristics of the receptor for another transmitter or modulator. Four types of interactions among transmission lines may be considered, but mainly intramembrane receptor-receptor interactions have been dealt with in this article, exemplified by the heteroregulation of D2 receptors via neuropeptide receptors and A2 receptors. The role of receptor-receptor interactions in the integration of signals is discussed, especially in terms of filtration of incoming signals, of integration of coincident signals, and of neuronal plasticity.

G-protein-coupled receptor heteromer dynamics

“…Additional in vivo studies, which examined the interactions of clonidine (a partial agonist for a 2A -ARs) and neuropeptide Y (NPY; a 36 amino acid neurotransmitter) on sleep-wakefulness cycles and arterial blood pressure control in both normal and spontaneously hypertensive rats (Fuxe et al, 1989;Fuxe, 1990;Yang et al, 1994), further supported the existence of receptor-receptor interactions and their potential functional relevance. As a logical consequence for the indications of direct physical interactions between neuropeptide and monoamine receptors, the term heteromerization was introduced to describe a specific interaction between different types of GPCRs (Zoli et al, 1993). The concept of the GPCR heterodimer was later confirmed by studies reporting that two non-functional GPCR monomers, GABA B1 and GABA B2 , can assemble in signaling heterodimers at the cell surface to transmit the inhibitory effect of the g-aminobutyric acid (GABA) neurotransmitter (Marshall et al, 1999): when expressed alone, the GABA B1 receptor is retained in the endoplasmic reticulum, and is able to reach the cell surface and bind GABA only in the presence of its partner, the GABA B2 receptor.…”

“…through allosteric interactions) in the plasma membrane (Agnati et al, 1982;Zoli et al, 1993). It was proposed that an RM functions as an integrated unit with unique signaling properties that are modulated by receptor-receptor allosteric interactions.…”

“…D 2 -receptor-mediated intracellular responses . The binding of ligand to one receptor altering the activation of the partner receptor in the heterodimer complex led to the hypothesis that conformational changes induced by ligand binding to one receptor might be transmitted to the receptor partner to modulate its function (Zoli et al, 1993).…”

Molecular Mechanisms and Therapeutical Implications of Intramembrane Receptor/Receptor Interactions among Heptahelical Receptors with Examples from the Striatopallidal GABA Neurons

“…In 1993 (Zoli et al, 1993), the hypothesis was introduced that the molecular mechanism for these large numbers of intramembrane receptor/receptor interactions among GPCR could be the formation of heteromeric complexes, the simplest being a heterodimer. This concept was based on the indication at the time that dimerization upon agonist activation may be a general phenomenon essential for receptor activation (Hollenberg, 1991), the best example being the dimerization of tyrosine kinase receptors (Schlessinger 1988(Schlessinger , 2000Helldin 1995).…”

“…Thus, it was assumed that GPCR exist mainly as homodimers that interact with other types of homodimers to form heterodimers. The relative proportions of homo-and heterodimers would be determined by the concentrations of the two transmitters, the density of the two receptors and their distribution patterns, and the unique features of each receptor/receptor interaction (Zoli et al, 1993). In fact, early evidence obtained on purified GPCR by, e.g., Venter and Fraser (1983) and Conn et al (1982) indicated that the functional GPCR were in a dimeric state.…”