Ion channel structure, function, regulation, disease mechanisms and drug discovery.

Ion channels are the fundamental elements for the generation and conduction of electrical and chemical signals in living organisms. Genetic mutations, malfunction and dysregulation of ion channels lead to numerous diseases and disorders. Therefore, ion channels are one of the main drug targets. The Yang Laboratory employs a variety of cutting-edge technologies to conduct the following research:

1. Generate primate and mouse models of neurological diseases caused by mutations in ion channels, including autism, epilepsy, and pain.

2. Study the molecular and cellular pathogenic mechanisms of these disease models from embryonic to adult stages.

3. Isolate or synthesize natural products from Chinese herbal medicine, test their effects on relevant ion channels, and study the action mechanisms of promising compounds on their ion channel targets.

4. Evaluate the efficacy of the most promising active molecules in mouse and primate disease models, and conduct preclinical studies.

Major contributions to Science:

Dr. Jian Yang is an established scholar in the field of ion channels and has made important or breakthrough discoveries in ion channel structure, function, regulation, disease mechanisms, and the exploration of natural active molecules. His major contributions to science include the following:

1. Identification of the selectivity filter as a gate in inward rectifier potassium (Kir) channels: Kir channels play a critical role in controlling/regulating neuronal excitability. Using cysteine chemical modification, Dr. Yang’s group discovered that the Kir channel pore is 12 Å wide (Lu et al., 1999a). They also demonstrated that the cytoplasmic domains of Kir channels form a long and wide intracellular vestibule that protrudes beyond the membrane into the cytoplasm (Lu et al., 1999b). Both findings were later confirmed by Kir channel structures obtained by other laboratories. Moreover, using the cutting-edge technology of unnatural amino acid mutagenesis, they engineered artificial amino acids into Kir channels and demonstrated directly that the selectivity filter is dynamic and regulates Kir channel gating (Lu et al., 2001). This work indicates that the selectivity filter of Kir channels can function as a gate, a conclusion further supported by their later work with chemicla modification (Xiao et al., 2003).

2. Structure, function and regulation of voltage-gated calcium channels (VGCCs): VGCCs are essential for life. Dysfunction and misregulation of VGCCs cause numerous diseases and disorders, including arrhythmia, hypertension, migraine and epilepsy. Dr. Yang’s group made three major discoveries in past studies on VGCCs: (1) They were the first to discover that VGCCs are regulated by PI(4,5)P₂ (Wu et al., 2002), providing mechanistic insights into the regulation of VGCCs by Gq-coupled receptors. (2) They were one of the three groups that simultaneously solved the first crystal structure of the beta subunit of VGCCs (Chen et al., 2004), which is essential for trafficking VGCCs to the plasma membrane and fine-tuning their biophysical properties. The structure overturns a then long-held and widely accepted doctrine regarding where and how alpha 1 and beta subunits interact. (3) They discovered that the alpha 1 subunit of neuronal L-type VGCCs undergoes a novel form of age- and activity-dependent proteolysis (called midchannel proteolysis) in the pore-forming core region (Michailidis et al., 2014), providing novel molecular insights into neuronal calcium homeostasis and neuroprotection. Each of these discoveries leads to new concepts and new research projects.

3. Assembly of TRPP/PKD complexes: The TRPP/PKD complexes play critical roles in calcium signaling in many cell types. Genetic mutations in these complexes cause human diseases, such as autosomal dominant polycystic kidney disease (ADPKD), one of the most common genetic diseases in humans. Using a multipronged approach Dr. Yang and collaborators have elucidated the molecular mechanisms of the assembly of TRPP2/PKD1 and TRPP3/PKD1L3 complexes (Yu et al., 2009; Jiang et al., 2011; Yu et al., 2012). Before their work, the prevailing view in the PKD field was that PKD proteins are membrane receptors, not ion channels, and that they play a regulatory role in TRPP/PKD complexes. Dr. Yang and colleagues’ work reveals, for the first time, that TRPP/PKD complexes have an odd stoichiometry, containing three TRPP subunits and one PKD subunit, and that PKDs are in fact channel-forming proteins that directly line the pore of TRPP/PKD complexes. These findings have later been confirmed by cryo-EM structures of TRPP/PKD complexes from other laboratories.

4. Structural basis of CNG channel properties and channelopathy: Cyclic nucleotide-gated (CNG) channels convert chemical signals into electrical signals and are essential for vision and smell. Numerous inherited mutations in rod and cone photoreceptor CNG channels are associated with degenerative visual disorders such as retinitis pigmentosa and achromatopsia. In 2017 Dr. Yang and collaborators obtained the first high-resolution structure of a full-length eukaryotic homotetrameric CNG channel (Li et al., 2017). They subsequently obtained the first high-resolution structures of both closed and open states of the same eukaryotic CNG channel (Zheng et al., 2020), which illuminate the conformational changes underpinning CNG channel activation and reveal a previously undescribed gate located in the central cavity. Dr. Yang’s group later determined the first high-resolution structure of the human cone photoreceptor CNG channel, a heterotetrameric channel formed by CNGA3 and CNGB3 subunits (Zheng et al., 2022a). This structure reveals features not observed in homomeric CNG channels and highlights a critical role of CNGB3 in shaping cone CNG channel properties and responses. Taking advantage of these newly gained structural information, Dr. Yang’s group elucidated the structural and functional effects of a disease mutation in the cone CNG channel and uncovered unexpected findings that have implications for investigating and treating retinopathy (Zheng et al., 2022b). Most recently, they obtained not only closed and open state but also intermediate /transition state structures of the human CNGA3/CNGB3 channel, illuminating the conformational landscape of ligand activation CNG channels. These studies provide significant insights into CNG channel ion permeation, gating and channelopathy.

2004 – 2008    Established Investigator Award, The American Heart Association

2001 – 2004     EJLB Scholar, The EJLB Foundation

2000 – 2003    McKnight Scholar Award, The McKnight Endowment Fund for Neuroscience

1997 – 1999     Sloan Research Fellow, Alfred P. Sloan Foundation

* for co-author; #for co-corresponding author.

1. Hu, Z., and Yang, J.(2023). Structural basis of properties, mechanisms and channelopathy of cyclic nucleotide-gated channels (invited review). Channels 17:1, DOI: 10.1080/19336950.2023.2273165(PMCID: PMC10761061)

2. Hu, Z., Zheng, X., and Yang, J.(2023). Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel. Nat. Commun. 13:4284. https://doi.org/10.1038/s41467-023-39971-8. (PMCID: PMC10354024)

3. Su, D.*, Gong, Y.*, Li, S.*, Yang, J.^#and Nian. Y.^#(2022). Cyclovirobuxine D, a cardiovascular drug from traditional Chinese medicine, alleviates inflammatory and neuropathic pain mainly via inhibition of voltage-gated Cav3.2 channels. Front. Pharmacol. https://doi.org/10.3389/fphar.2022.1081697

4. Zheng, X.*, Li, H.*, Hu, Z.*, Su, D. and Yang, J.(2022). Structural and functional characterization of an achromatopsia-associated mutation in a phototransduction channel. Commun. Biol.5, 190. https://doi.org/10.1038/s42003-022-03120-6 X

5. Zheng, X., Hu, Z., Li, H., and Yang, J.(2022). Structure of the human cone photoreceptor cyclic nucleotide-gated channel. Nat. Struc. Mol. Biol.29, 40-46. (PMCID: PMC8776609)

6. Jia, Q.*, Tian, W.*, Li, B.*, Chen, W.*, Zhang, W.*, Xie, Y., Cheng, N., Chen, Q., Xie, J.^#,  Zhang, Y.^#, Yang, J.^#, and Wang, S.^#(2021) Transient Receptor Potential channels, TRPV1 and TRPA1 in melanocytes synergize UV-dependent and UV-independent melanogenesis. Br. J. Pharmacol. 178, 4646-4662.

7. Zheng, X.*, Fu, Z.*, Su, D.*, Zhang Y., Li, M., Pan, Y., Li, H., Li, S., Grassucci, R.A., Ren, Z, Hu, Z., Li, X., Zhou, M., Li, G. ^#, Frank, J. ^#, and Yang, J.^#(2020). Mechanism of ligand activation of a eukaryotic cyclic nucleotide-gated channel. Nat. Struc. Mol. Biol.27, 625-634. (PMCID: PMC7354226)

8. Ye, Y.S.*, Li, W.Y.*, Du, S.Z.*, Yang, J^. #, Nian, Y^{. #}, and Xu, G^{. #}(2020). Congenetic Hybrids Derived from Dearomatized Isoprenylated Acylphloroglucinol with Opposite Effects on C_av3.1 Low Voltage-Gated C^a2+Channel. J. Med. Chem.63, 1709-1716.

9. Zhou, X.*, Li, M-H.*, Su, D.*, Li, H., Jia, Q., Li, X.^#, and Yang, J.^#(2017). Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states. Nat. Struc. Mol. Biol. 24, 1146-1154.  (PMCID: PMC5747366)

10. Jiang, H-H.*, Dong, F-W. *., Zhou, J., Hu, J-M.^#, Yang, J.^#, and Nian, Y.^#(2017). Ca_v2.2 and Ca_v3.1 calcium channel inhibitors fromValeriana jatamansi Jones. RSC Adv. 7, 45878-45884.

11. Wang, S.*^#, Zhang, D.^*, Hu, J.^*, Xu, W.^*, Su, D., Xu, Z., Cui, J., Zhou, M., Yang, J.^#, and Xiao, J.^#  (2017). Clinical and mechanistic study of Bingpian, a topical analgesic in traditional Chinese medicine. EMBO Mol. Med. 9, 205-213. (PMCID: PMC5452010)

12. Li, M-H.*, Zhang, W,K.*, Benvin, N*., Zhou, X., Su, D., Wang, S., Michailidis, I.E., Tong, L., Li, X., and Yang, J. (2017). Structural basis of Ca²⁺/pH dual regulation of the endolysosomal Ca²⁺channel TRPML1. Nat. Struc. Mol. Biol.24, 205-213. (PMCID: PMC5336481)

13. Li, M.*, Zhou, X.*, Wang, S.*, Michailidis, I.E., Gong, Y., Su, D., Li, H., Li, X.^#, and Yang, J.^#(2017). Structure of a eukaryotic cyclic nucleotide-gated channel. Nature542, 60-65. (PMCID: PMC5783306)

14. Zhou, F.J., Nian, Y., Yan, Y., Gong, Y., Luo, Q., Zhang,Y., Hou, B., Zuo, Z.L., Wang, S.M., Jiang, H.H., Yang, J. ^#, and Cheng, Y.X.^#(2015). Two new classes of T-type calcium channel inhibitors with new chemical scaffolds from Ganoderma cochlear. Org. Lett. 17, 3082-3085.

15. Michailidis, I.E., Abele, K., Zhang, W.K., Lin, B., Yu, Y., Geyman, L., Ehlers, M.D., Pnevmatikakis, E.A., and Yang J.(2014). Age-related homeostatic midchannel proteolysis of L-type voltage-gated Ca²⁺ channels. Neuron82, 1045-1057. (PMCID: PMC4052215)

16. Yu, Y., Ulbrich, M.H., Dobbins, S. Li, M-h., Zhang, W.K., Tong, L., Isacoff, E.Y., and Yang, J.(2012). Molecular mechanism of the assembly of an acid-sensing receptor/ion channel complex. Nat. Commun.3:1252. doi: 10.1038/ncomms2257. (PMCID: PMC3575195)

17. Buraei, Z., and Yang, J. (2010). The b subunit of voltage-gated Ca²⁺channels (invited review). Physiological Reviews 90, 1461-1506.

18. Fan, M-m.*, Buraei, Z.*, Luo, H-R., Levenson-Palmer, R., and Yang, J.(2010). Direct inhibition of P/Q-type voltage-gated Ca²⁺channels by Gem does not require a direct Gem/Ca_vβ interaction. Proc. Natl. Acad. Sci. 107, 14887-14892. (PMCID: PMC2930421)

19. Yu, Y., Ulbrich, M.H., Li, M-h., Chen, X-Z., Ong, A.C.M., Tong, L., Isacoff, E.Y., and Yang, J.(2009). Structural and molecular basis of the assembly of the TRPP2/PKD1 complex. Proc. Natl. Acad. Sci. 106, 11558-11563. (PMCID: PMC2710685)

20. Zhang, Y., Chen, Y-h., Bangaru, S.D., Abele, K., Tanabe, S., Kozasa, T., and Yang, J.(2008). Origin of the voltage-dependence of G protein regulation of P/Q-type Ca²⁺channels. J. Neurosci.28, 14176-14188. (PMCID: PMC2685181)

21. Chen, Y-h., Li, M-h., Zhang, Y.,  He., L-l., Yamada, Y., Fitzmaurice, A., Shen, Y., Zhang, H., Tong, L., and Yang, J.(2004). Structural basis of the a₁-b interaction of voltage-gated Ca²⁺channels. Nature429, 675-680.

22. Xiao, J., Zhen, X-G., and Yang, J.(2003). Localization of PIP₂activation gate in inward rectifier K⁺channels. Nature Neurosci.6, 811-818.

23. Wu, L.*, Bauer, C*., Zhen, X-G., Xie, C., and Yang, J.(2002). Dual regulation of voltage-gated calcium channels by PIP₂. Nature 419, 947-952.

24. Lu, T., Ting, A.Y., Mainland, J., Jan, L.Y., Schultz, P.G., and Yang, J. (2001). Probing ion permeation and gating in a K⁺channel with backbone mutations in the selectivity filter. Nature Neurosci. 4, 239-246.

25. Yang, J., Ellinor, P.T., Sather, W.A., Zhang, J.F., and Tsien, R.W. (1993). Molecular determinants of Ca2+ selectivity and ion permeation in L-type Ca2+ channels. Nature 386, 158-161.