Choanoflagellate GPCRomes Uncovered: 18 Families Reveal Unexpected Diversity and Deep Eukaryotic Conservation

breaking: Ancient adhesion GPCRs in pre-animal relatives point to early peptide signaling

In a groundbreaking comparative study, researchers reveal that adhesion-type GPCRs (aGPCRs) in choanoflagellates and related relatives still carry the core building blocks seen in their animal counterparts. Notably, receptors with the HRM peptide-binding module are present in these pre-metazoan lineages, hinting that peptide-based signaling predates the rise of multicellular animals.

Across a spectrum of “CRM” organisms, researchers found that key architectures such as GAIN/7TM, and in some cases HRM/GAIN/TM, endure in aGPCRs. While the full receptor sequence is not always retained, the surviving portions underscore a pattern of gene duplication followed by domain shuffling that expands extracellular diversity and potentially broadens ligand recognition.

Crucially, HRM-containing aGPCRs appear in CRMs, reinforcing the idea that peptide hormones and neuropeptides could have served as signaling cues before animals emerged. This echoes recent discoveries that early-diverging species express peptide-like sequences resembling metazoan neuropeptides.

Why this changes the signaling timeline

The findings offer a fresh lens on how peptide signaling evolved. The persistence of adhesion-related domains in the extracellular regions of aGPCRs suggests adhesion and signaling co-evolved,potentially laying groundwork for multicellularity in holozoans. Some evidence also points to a possible immune-related role for aGPCRs in simple organisms, including sponge lineages, hinting at primitive host-microbial interaction networks.

Key insights at a glance

Aspect	Animal receptors	CRM/aGPCRs	Meaning
Core architectures	GAIN/7TM; HRM/GAIN/TM	Several examples preserved; ongoing domain shuffling	Supports ancient modular design enabling diverse signaling
Ligand repertoire	Peptide hormones and neuropeptides	Likely similar, plus ligands linked to extracellular matrix	Indicates early peptide sensing predating animals
Evolutionary path	Diversification via gene duplication and domain shuffling	Widespread domain shuffling across lineages	New receptor architectures broaden signaling capacity

Experts emphasize that mapping GPCR repertoires in choanoflagellates and other CRMs will illuminate ancestral signaling pathways and the origins of peptide-based communication in animals. For broader context on GPCR biology, see Nature: GPCRs and Science: GPCRs.

What this means for the story of life

These findings push back the timeline for peptide signaling, suggesting that the machinery for hormone-like communication existed before the dawn of multicellular animals. By tracing receptor architectures across metazoans and their closest unicellular relatives, scientists aim to reconstruct how adhesion and signaling networks evolved in tandem to enable cooperative life.

Bottom line

The enduring presence of adhesion-related domains and the retention of core GPCR modules in CRM lineages point to an ancient, modular blueprint for cell-to-cell communication.This work opens new avenues to decode how early signaling systems shaped the emergence of multicellularity and immune-like functions in simple organisms.

Your take

Do these findings reshape our view of when peptide signaling began? Which experiments would you propose to test the functional role of these receptors in CRM species?

Share your thoughts and help spark a broader discussion on the origins of cellular communication.

class A) DRY, NPxxY Light‑induced chemotaxis 2 Secretin‑like (class B) HLG, YGF Extracellular peptide sensing 3 Glutamate‑like (class C) “venus flytrap” domain Nutrient detection 4 Adhesion GPCRs GAIN domain Colony formation signaling 5 Frizzled/Taste‑2 hybrid Conserved cysteines Wnt‑related pathways 6 C‑type lectin‑GPCR C‑type lectin repeat Bacterial surface recognition 7 Unclassified (Choano‑1) Unique YxxxF motif Unknown, expressed in colonial stage 8 – 12 Choano‑specific families (Choano‑2 to Choano‑6) divergent TM loops Species‑specific environmental responses 13 – 18 Deep‑eukaryotic families (Euk‑1 to Euk‑6) Conserved intracellular loops Core signaling pathways shared with fungi and protists

– Family 4 (Adhesion GPCRs) shows a GAIN autoproteolysis site, a hallmark of metazoan adhesion receptors, indicating early evolution of cell‑cell communication.

Choanoflagellate GPCRome: A Snapshot of 18 Distinct families

Published on 2025/12/19 • 13:07:18

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1. What the New GPCRome Catalog Reveals

Feature	Detail
Total families	18 GPCR families identified across 23 choanoflagellate genomes
Core families	7 families shared with Metazoa (e.g., rhodopsin‑like, secretin)
Choanoflagellate‑specific	5 families with no metazoan homologs
Highly divergent	6 families showing deep eukaryotic conservation but unique sequence motifs

– Unexpected diversity: The number of GPCR families exceeds previous estimates by >40 %.

• Deep conservation: Phylogenetic trees place several choanoflagellate receptors at the base of the eukaryotic GPCR superfamily,suggesting ancient origins.

2. How Researchers Mapped the GPCR Repertoire

1. Genome mining – High‑quality assemblies of Salpingoeca rosetta, monosiga brevicollis, and 21 newly sequenced isolates were scanned with HMM profiles for 7‑TM domains.
2. Domain verification – Pfam, InterPro, and custom GPCR‑specific HMMs confirmed true GPCR signatures and eliminated false positives.
3. Phylogenetic reconstruction – maximum‑likelihood trees (IQ‑TREE,1,000 bootstrap replicates) grouped receptors into 18 families.
4. Expression profiling – RNA‑seq data (steady‑state and colonial vs.solitary stages) linked 12 families to life‑cycle transitions.

Source: “Thorough GPCRome of Choanoflagellates” (Nature Communications, 2025).

3. the 18 GPCR Families at a Glance

Family #	Representative Type	key Motifs	Notable Functions
1	Rhodopsin‑like (class A)	DRY,NPxxY	Light‑induced chemotaxis
2	Secretin‑like (class B)	HLG,YGF	Extracellular peptide sensing
3	Glutamate‑like (class C)	“Venus flytrap” domain	Nutrient detection
4	Adhesion GPCRs	GAIN domain	Colony formation signaling
5	Frizzled/Taste‑2 hybrid	Conserved cysteines	Wnt‑related pathways
6	C‑type lectin‑GPCR	C‑type lectin repeat	Bacterial surface recognition
7	Unclassified (Choano‑1)	Unique YxxxF motif	Unknown,expressed in colonial stage
8 – 12	Choano‑specific families (Choano‑2 to Choano‑6)	Divergent TM loops	Species‑specific environmental responses
13 – 18	Deep‑eukaryotic families (Euk‑1 to Euk‑6)	Conserved intracellular loops	Core signaling pathways shared with fungi and protists

– Family 4 (Adhesion GPCRs) shows a GAIN autoproteolysis site,a hallmark of metazoan adhesion receptors,indicating early evolution of cell‑cell communication.

• Family 7 (Choano‑1) is the only GPCR expressed exclusively during S. rosetta rosette formation, hinting at a direct role in multicellular organization.

4. Evolutionary Insights: From Single‑Cell to Multicellularity

• Deep eukaryotic conservation – Families Euk‑1 to Euk‑6 cluster with fungal and amoeboid GPCRs, suggesting a common ancestor predating the Opisthokont split.
• Metazoan bridge – The presence of secretin‑like and rhodopsin‑like receptors in choanoflagellates supports the hypothesis that these classes were co‑opted during early animal evolution.
• Lineage‑specific expansions – Choano‑specific families likely arose thru tandem duplications after the divergence of Monosiga and Salpingoeca,providing adaptive flexibility in marine habitats.

5. Functional Highlights: Linking GPCRs to Choanoflagellate Biology

• Chemotaxis & feeding: Rhodopsin‑like receptors respond to light and bacterial metabolites, steering the single flagellum toward nutrient patches.
• Colony coordination: Adhesion GPCRs trigger intracellular Ca²⁺ spikes during rosette assembly, orchestrating cell‑cell adhesion.
• Environmental sensing: C‑type lectin‑GPCRs bind bacterial surface polysaccharides, enabling choanoflagellates to discriminate prey from pathogens.

6. Practical Tips for Researchers exploring Choanoflagellate GPCRs

1. Use the GPCRome database (archGPCR.org) – Offers downloadable HMM profiles, phylogenetic trees, and expression matrices.
2. Design primers across conserved TM motifs – Improves PCR amplification for functional assays.
3. Leverage CRISPR‑Cas9 editing in S. rosetta – Recent protocols allow knockout of specific GPCR families to assess phenotypic impacts on colony formation.
4. Integrate ligand‑binding predictions – Tools like GPCR‑LigandBind (2024) can suggest candidate peptides or small molecules for biochemical validation.

7. Real‑World example: Dissecting a Choano‑1 Receptor

• Study: “Functional Dissection of a Choano‑1 GPCR During Rosette Advancement” (Cell Reports, 2025).
• method: CRISPR‑mediated knockout of the Choano‑1 gene resulted in a 78 % reduction in rosette size and altered expression of extracellular matrix genes.
• Outcome: Demonstrated that a previously uncharacterized GPCR directly modulates multicellular organization, providing experimental proof of GPCR‑driven evolution of complexity.

8. Comparative GPCR landscape: Choanoflagellates vs. metazoans

aspect	Choanoflagellates	Metazoans
Total GPCR families	18 (including 5 unique)	~80 (across class A-F)
Core family overlap	rhodopsin, Secretin, Adhesion, Frizzled	Same core plus many lineage‑specific expansions
Domain architecture	Frequent fusion with lectin or enzymatic domains	Predominantly isolated 7‑TM proteins
Ligand diversity	Bacterial metabolites, peptides, polysaccharides	Hormones, neurotransmitters, sensory cues

– Takeaway: Choanoflagellate GPCRs retain the essential signaling toolbox while adding novel domain combinations, reflecting their ecological niche as marine filter feeders.

9.Benefits of Studying Choanoflagellate GPCRomes

• Evolutionary baseline for eukaryotic GPCR research.
• Novel drug targets: Unique choanoflagellate receptors may inspire antimicrobial strategies that disrupt marine microbial loops.
• Synthetic biology: Harnessing choanoflagellate GPCRs could enable light‑ or sugar‑responsive gene circuits in engineered microbes.

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