8.A.47 The Neuropilin and Tolloid-like (Neto) Family 

Kainate receptors are a family of ionotropic glutamate receptors whose physiological roles differ from those of other subtypes of glutamate receptors in that they predominantly serve as modulators, rather than mediators, of synaptic transmission (Copits and Swanson 2012). Neuronal kainate receptors exhibit unusually slow kinetic properties that have been difficult to reconcile with the behaviour of recombinant kainate receptors. However, the neuropilin and tolloid-like 1 (NETO1) and NETO2 proteins are auxiliary kainate receptor subunits that shape both the biophysical properties and synaptic localization of these receptors (Howe 2014). Several members of this family are large (700 - 900 aas; ~ twice as large as the monodomain proteins), and they contain at least two domains, an N-terminal domain belonging to TC family 8.A.47, and a fused domain belonging to TC family 8.A.154.  In view of this fact, it can be surmised that the members of these two families may function together.

Neto2 also interacts with the neuron-specific K+-Cl- cotransporter (KCC2) in the central nervous system (CNS). Efficient KCC2 transport is essential for setting the neuronal Cl- gradient, which is required for fast GABAergic inhibition. Neto2 is required to maintain the normal abundance of KCC2 in neurons, and increases KCC2 function by binding to the active oligomeric form of this cotransporter (Mahadevan et al. 2015). The amino-terminal domains of GluK1 and GluK2 control the strikingly different trafficking properties between these two receptors and are critical for synaptic expression of heteromeric receptors at mossy fiber-CA3 synapses. They also mediate the differential dependence on Neto proteins for surface and synaptic trafficking of GluK1 and GluK2 (Sheng et al. 2017) and regulate interneuronal somatodendritic and presynaptic kainate receptors to control network inhibition (Wyeth et al. 2017).

Kainate receptor heteromerization with the auxiliary subunits, Neto1 and Neto2, attenuate polyamine ion-channel block by facilitating polyamine permeation (Brown et al. 2016). Relief of polyamine block in GluK2/GluK5 heteromers results from a key proline residue that produces architectural changes in the channel pore α-helical region. The neto auxiliary subunits exert an additive effect to heteromerization, and thus relieve the polyamine block.




Bosseboeuf, E., A. Chikh, A.B. Chaker, T.P. Mitchell, D. Vignaraja, R. Rajendrakumar, R.S. Khambata, T.D. Nightingale, J.C. Mason, A.M. Randi, A. Ahluwalia, and C. Raimondi. (2023). Neuropilin-1 interacts with VE-cadherin and TGFBR2 to stabilize adherens junctions and prevent activation of endothelium under flow. Sci Signal 16: eabo4863.

Brown, P.M., M.R. Aurousseau, M. Musgaard, P.C. Biggin, and D. Bowie. (2016). Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. J. Physiol. 594: 1821-1840.

Copits, B.A. and G.T. Swanson. (2012). Dancing partners at the synapse: auxiliary subunits that shape kainate receptor function. Nat Rev Neurosci 13: 675-686.

Dutta, S., N.S. Polavaram, R. Islam, S. Bhattacharya, S. Bodas, T. Mayr, S. Roy, S.A.Y. Albala, M.I. Toma, A. Darehshouri, A. Borkowetz, S. Conrad, S. Fuessel, M. Wirth, G.B. Baretton, L.C. Hofbauer, P. Ghosh, K.J. Pienta, D.L. Klinkebiel, S.K. Batra, M.H. Muders, and K. Datta. (2022). Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer. Oncogene. [Epub: Ahead of Print]

Gomez, K., P. Duran, R. Tonello, H.N. Allen, L. Boinon, A. Calderon-Rivera, S. Loya-López, T.S. Nelson, D. Ran, A. Moutal, N.W. Bunnett, and R. Khanna. (2023). Neuropilin-1 is essential for vascular endothelial growth factor A-mediated increase of sensory neuron activity and development of pain-like behaviors. Pain. [Epub: Ahead of Print]

He, L., J. Sun, Y. Gao, B. Li, Y. Wang, Y. Dong, W. An, H. Li, B. Yang, Y. Ge, X.C. Zhang, Y.S. Shi, and Y. Zhao. (2021). Kainate receptor modulation by NETO2. Nature 599: 325-329.

Hou, L. and Y. Du. (2023). Neuropilin 1 Promotes Unilateral Ureteral Obstruction-Induced Renal Fibrosis via RACK1 in Renal Tubular Epithelial Cells. Am. J. Physiol. Renal Physiol. [Epub: Ahead of Print]

Howe, J.R. (2014). Modulation of non-NMDA receptor gating by auxiliary subunits. J. Physiol. [Epub: Ahead of Print]

Issitt, T., E. Bosseboeuf, N. De Winter, N. Dufton, G. Gestri, V. Senatore, A. Chikh, A.M. Randi, and C. Raimondi. (2019). Neuropilin-1 Controls Endothelial Homeostasis by Regulating Mitochondrial Function and Iron-Dependent Oxidative Stress. iScience 11: 205-223.

Kong, W., M. Montano, M.J. Corley, E. Helmy, H. Kobayashi, M. Kinisu, R. Suryawanshi, X. Luo, L.A. Royer, N.R. Roan, M. Ott, L.C. Ndhlovu, and W.C. Greene. (2022). Neuropilin-1 Mediates SARS-CoV-2 Infection of Astrocytes in Brain Organoids, Inducing Inflammation Leading to Dysfunction and Death of Neuron.s. mBio e0230822. [Epub: Ahead of Print]

Li, Y.J., G.F. Duan, J.H. Sun, D. Wu, C. Ye, Y.Y. Zang, G.Q. Chen, Y.Y. Shi, J. Wang, W. Zhang, and Y.S. Shi. (2019). Neto proteins regulate gating of the kainate-type glutamate receptor GluK2 through two binding sites. J. Biol. Chem. 294: 17889-17902.

Mahadevan, V., Z. Dargaei, E.A. Ivakine, A.M. Hartmann, D. Ng, J. Chevrier, J. Ormond, H.G. Nothwang, R.R. McInnes, and M.A. Woodin. (2015). Neto2-null mice have impaired GABAergic inhibition and are susceptible to seizures. Front Cell Neurosci 9: 368.

Malik, J.R., A. Acharya, S.N. Avedissian, S.N. Byrareddy, C.V. Fletcher, A.T. Podany, and S.R. Dyavar. (2023). ACE-2, TMPRSS2, and Neuropilin-1 Receptor Expression on Human Brain Astrocytes and Pericytes and SARS-CoV-2 Infection Kinetics. Int J Mol Sci 24:.

Martinez-Martin, N., J. Marcandalli, C.S. Huang, C.P. Arthur, M. Perotti, M. Foglierini, H. Ho, A.M. Dosey, S. Shriver, J. Payandeh, A. Leitner, A. Lanzavecchia, L. Perez, and C. Ciferri. (2018). An Unbiased Screen for Human Cytomegalovirus Identifies Neuropilin-2 as a Central Viral Receptor. Cell 174: 1158-1171.e19.

McKay, J.P., D.M. Raizen, A. Gottschalk, W.R. Schafer, and L. Avery. (2004). eat-2 and eat-18 are required for nicotinic neurotransmission in the Caenorhabditis elegans pharynx. Genetics 166: 161-169.

Michishita, M., T. Ikeda, T. Nakashiba, M. Ogawa, K. Tashiro, T. Honjo, K. Doi, S. Itohara, and S. Endo. (2004). Expression of Btcl2, a novel member of Btcl gene family, during development of the central nervous system. Brain Res Dev Brain Res 153: 135-142.

Sheng, N., Y.S. Shi, and R.A. Nicoll. (2017). Amino-terminal domains of kainate receptors determine the differential dependence on Neto auxiliary subunits for trafficking. Proc. Natl. Acad. Sci. USA 114: 1159-1164.

Walker, C.S., M.M. Francis, P.J. Brockie, D.M. Madsen, Y. Zheng, and A.V. Maricq. (2006). Conserved SOL-1 proteins regulate ionotropic glutamate receptor desensitization. Proc. Natl. Acad. Sci. USA 103: 10787-10792.

Walker, C.S., P.J. Brockie, D.M. Madsen, M.M. Francis, Y. Zheng, S. Koduri, J.E. Mellem, N. Strutz-Seebohm, and A.V. Maricq. (2006). Reconstitution of invertebrate glutamate receptor function depends on stargazin-like proteins. Proc. Natl. Acad. Sci. USA 103: 10781-10786.

Wyeth, M.S., K.A. Pelkey, X. Yuan, G. Vargish, A.D. Johnston, S. Hunt, C. Fang, D. Abebe, V. Mahadevan, A. Fisahn, M.W. Salter, R.R. McInnes, R. Chittajallu, and C.J. McBain. (2017). Neto Auxiliary Subunits Regulate Interneuron Somatodendritic and Presynaptic Kainate Receptors to Control Network Inhibition. Cell Rep 20: 2156-2168.

Zheng, Y., J.E. Mellem, P.J. Brockie, D.M. Madsen, and A.V. Maricq. (2004). SOL-1 is a CUB-domain protein required for GLR-1 glutamate receptor function in C. elegans. Nature 427: 451-457.


TC#NameOrganismal TypeExample

Neuropilin and tolloid-like 1 (Neto1 or BTCL1) protein of 533 aas and 2 TMSs (Copits and Swanson 2012; Howe 2014). It is involved in the development and/or maintenance of neuronal circuitry and is an accessory subunit of the neuronal N-methyl-D-aspartate receptor (NMDAR), critical for maintaining the abundance of GRIN2A-containing NMDARs in the postsynaptic density. It also regulates long-term NMDA receptor-dependent synaptic plasticity and cognition, at least in the context of spatial learning and memory (Michishita et al. 2004).


Neto 1 of Homo sapiens


Neuropilin and tolloid-like protein 2, Neto2 (Neto-2; Neto 2) or BTCL2, of 525 aas and 2 TMSs, one N-terminal and a second near the C-terminus of the protein (Copits and Swanson 2012). It is an accessory subunit of neuronal kainate-sensitive glutamate receptors, GRIK2 and GRIK3. It increases kainate-receptor channel activity, slowing the decay kinetics of the receptors, without affecting their expression at the cell surface, and increasing the open probability of the receptor channels. It modulates the agonist sensitivity of kainate receptors and slows the decay of kainate receptor-mediated excitatory postsynaptic currents (EPSCs), thus directly influencing synaptic transmission. Neto1 and Neto2 are auxiliary subunits of kainate-type glutamate receptors (KARs) that regulate KAR trafficking and gating (Li et al. 2019). CryoEM structures of homotetrameric GluK2 in complex with NETO2 have been published; NETO2 accesses two broad faces of kainate receptors (He et al. 2021).



Neto2 pf Homo sapiens


Procollagen C-endopeptidase enhancer 1 isoform X2 of 477 aas and 1 N-terminal TMS.

Peptidase of Urocitellus parryii (Arctic ground squirrel)


Supressor of lurcher protein, Sol-1, of 594 aas and 2 TMSs, one N-terminal and one C-terminal.  Sol1 is an accessory protein required for glutamate-gated currents that participate in the gating of non-NMDA (N-methyl-D-aspartate) ionotropic glutamate receptors such as Glr-1. It is predicted to contain four extracellular beta-barrel-forming domains known as CUB domains. SOL-1 and GLR-1 colocalize to the cell surface and can be co-immunoprecipitated. By recording from neurons expressing GLR-1, SOL-1 is selectively required for glutamate-gated currents (Zheng et al. 2004) and regulates desensitization (Walker et al. 2006).

Sol-1 of Caenorhabditis elegans


Neuropilin-1, NRP1, of 923 aas and 2 TMSs, N- and C-terminal. NRP1 localizes to mitochondria and interacts with the mitochondrial transporter, ABCB8 (TC# 3.A.1.201.22). NRP1 loss reduces ABCB8 levels, resulting in iron accumulation, iron-induced mitochondrial superoxide production, and iron-dependent EC senescence. The region of this protein that is homologous to other members of the Neuropilin (Neto) family are residues 26 to 245. Then there is a repeat sequence of about 120 residues, from 278 to 424 and repeated in residues 436 to 583. Residues 601 to the end show similarity to Meprin A (TC#8.A.77.2.1). NRP1 regulates mitochondrial iron transport via interaction with ABCB8/MITOSUR (Issitt et al. 2019). Neuropilin-1 mediates SARS-CoV-2 infection of astrocytes in brain organoids, inducing inflammation leading to dysfunction and death of neurons (Kong et al. 2022). Angiotensin converting enzyme 2 (ACE-2), transmembrane serine protease 2 (TMPRSS-2) and Neuropilin-1 cellular receptors support the entry of SARS-CoV-2 into susceptible human target cells including astrocytes in the blood brain barrier (BBB) (Malik et al. 2023). Neuropilin-1 interacts with VE-cadherin and TGFBR2 to stabilize adherens junctions and prevent activation of an endothelium under flow; it more generally stabilizes protein complexes at cell-cell junctions while supression endothelial inflamation (Bosseboeuf et al. 2023). Neuropilin-1 is essential for vascular endothelial growth factor A-mediated increase of sensory neuron activity and development of pain-like behaviors (Gomez et al. 2023).  Neuropilin 1 promotes unilateral ureteral obstruction-induced renal fibrosis via RACK1 in Renal tubular epithelial cells (Hou and Du 2023).



NRP1 of Homo sapiens


Neuropilin-2 of 931 aas and 2 TMSs, N- and C-terminal. It is a high affinity receptor for semaphorins 3C, 3F, VEGF-165 and VEGF-145 isoforms of VEGF, and the PLGF-2 isoform of PGF. It acts as a receptor for human cytomegalovirus pentamer-dependent entry in epithelial and endothelial cells (Martinez-Martin et al. 2018). Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer (Dutta et al. 2022).

Neuropilin-2 of Homo sapiens


Proteinase R of 665 aas and 1 N-terminal TMS.

Proteinase R of Holothuria leucospilota


Tolloid-like protein 1 isoform X4 of 822 aas and 2 TMSs, N- and C-terminal.

Tolloid-like protein of Solenopsis invicta (red fire ant)


TC#NameOrganismal TypeExample