GPCR heteromers can be detected using three main approaches.
(a) Fluorophore-coupled ligand-mediated FRET. Fluorophore-coupled ligands for two receptors can be analyzed using FRET only if their two cognate receptors are in close proximity in a heteromeric complex.
(b) Heteromer-selective antibodies that recognize only heteromers can be used to study the localization and levels of heteromers.
(c) Heteromer-specific ligands can bind only to the altered receptor binding pocket formed in a heteromer.
GPCR heteromers can be modulated using six main approaches.
(d) Heteromer-specific agonists can activate a receptor only if in a heteromeric form.
(e) Heteromer-specific antagonists can block a receptor only if in a heteromeric form.
(f) Heteromer-specific antibodies can block receptor binding and/or signaling only if in a heteromeric form.
(g) Activating heteromer-specific antibodies can activate receptors only if in a heteromeric form.
(h) Bivalent ligands can bind and activate receptors only if their cognate receptors are in a heteromer.
(i) The ligand of one receptor can act as a negative or positive allosteric modulator of the interacting receptor in a heteromer. The allosteric modulator can alter the binding and/or signaling properties of the interacting receptor.

(a) Heteromerization leads to the formation of an altered ligand binding site. Shown for DOR-KOR [15,37], DOR-MOR [14,17] and MOR-sst2A [54].
(b) Heteromerization leads to a decrease or increase in coupling to the G-protein. Decreased coupling was shown for the DOR-MOR heteromer [14]; increased coupling was shown for α2-AR-MOR [21], and AT1R-B2R [13].
(c) Heteromerization leads to coupling to a new G-protein. Shown for MOR-DOR heteromer coupling to Gαz [26,55]; heteromerization of two differently coupled receptors leads to preferential coupling to one G-protein upon co-stimulation. Shown for DOR-SNSR-4 [23].
(d) Heteromerization leads to a switch in receptor coupling, from G-protein to β-arrestin, and subsequent differential signaling and transcription factor activation. Shown for the MOR-DOR heteromer [28].