For all publications authored by Dr. Geoffrey W. Abbott, click here.
Notable publications in selected areas:
(i) Ligand activation of neuronal Kv channels by neurotransmitters and plant metabolites.
We recently discovered that neuronally expressed members of the influential Kv7 (KCNQ) family of voltage-gated potassium channels can be activated by direct binding of neurotransmitters and plant metabolites. Thus, Kv7.3 and Kv7.5 (and the predominant M-current molecular correlate, Kv7.2/3) are directly activated by GABA, the primary inhibitory neurotransmitter. More recently, we found that some modern and traditional medicines exploit the ligand sensitivity of Kv7 channels. We found that two components of an African folk anticonvulsant medicine (Mallotus oppositifolius leaf extract), mallotoxin and isovaleric acid, bind in the neurotransmitter binding pocket in Kv7.2/3 channels, and act synergistically there to open up the channel and prevent seizures. Most recently, we discovered the first known small molecules able to directly rescue Kv1.1 channel mutants linked to Episodic Ataxia 1 (EA1), from Native American ataxia medicines and found that carnosic acid from rosemary is a highly efficacious and heteromer-selective Kv7.3, Kv7.5 and Kv7.3/5 channel opener.
a. Manville R.W., Papanikolaou M., Abbott GW (2018). Direct neurotransmitter activation of voltage-gated potassium channels. Nature Communications. 9:1847. PMC5945843
b. Manville R.W., Abbott GW (2018). Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket. Nature Communications. 9: 3845 PMC6155021
c. Manville RW, Freites JA, Sidlow R, Tobias DJ, Abbott GW (2023) Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain. Nature Communications 14(1):3281. PMC10244465
d. Rían W Manville, Derk Hogenkamp, Geoffrey W Abbott (2023) Ancient medicinal plant rosemary contains a highly efficacious and isoform-selective KCNQ potassium channel opener. Communications Biology 6(1):644. PMC10272180
(ii) Ligand activation of other Kv channels by plant metabolites
We have also studied regulation by plant metabolites of Kv channels expressed in the heart, vasculature, epithelia, and T cells, and linked these molecular mechanisms to the therapeutic actions of traditional botanical medicines, a connection that was hitherto unsuspected. In 2018 we found a third, novel component of Mallotus leaf extract that activates the cardiac and epithelial Kv7.1 channel and narrowed down its binding site to a single residue at the foot of the voltage sensor, uncovering a new way to pharmacologically open voltage-gated potassium channels. We discovered in 2019 that KCNQ5 activation is a unifying mechanism for folk medicine anti-hypertensive plant extracts. In 2024, we discovered that two much-used herbal medicines contain small molecules that act on specific K+ channels, resulting in anti-inflammatory and analgesic actions.
a. De Silva, A., Manville, R.W., Abbott, GW (2018). Deconstruction of an African folk medicine uncovers a novel molecular strategy for therapeutic potassium channel activation. Science Advances 4(11):eaav0824. PMC6235520
b. Manville RW, van der Horst J, Redford KE, Katz BB, Jepps TA, Abbott GW (2019) KCNQ5 activation is a unifying molecular mechanism shared by genetically and culturally diverse botanical hypotensive folk medicines. Proc Natl Acad Sci 116 (42) 21236-21245 PMC6800379
c. Redford, KE, Abbott, GW. (2020). The ubiquitous flavonoid quercetin is an atypical KCNQ potassium channel activator. Communications Biology 3(1):356 PMC7343821
d. Manville RW, Yoshimura RF, Yeromin AV, Hogenkamp D, van der Horst J, Zavala A, Chinedu S, Arena G, Lasky E, Fisher M, Tracy CR, Othy S, Jepps TA, Cahalan MD, Abbott GW. (2024) Polymodal K+ channel modulation contributes to dual analgesic and anti-inflammatory actions of traditional botanical medicines. Communications Biology 7(1):1059. doi: 10.1038/s42003-024-06752-y. PMID: 39198706
(iii) Ligand activation of neuronal Kv channels by endogenous metabolites and synthetic compounds
Further expanding the known pharmacology of Kv7 and Kv1 channels, we discovered that the primary ketone body generated when on a ketogenic diet – β-hydroxybutryric acid (BHB) – also directly activates Kv7.2/3 channels. This suggests a potential role for BHB activation of Kv7.2/3 in the anticonvulsant effects of the ketogenic diet. In addition, we found that the blockbuster pain drug gabapentin activates Kv7.3, 5 and 2/3 channels in the nanomolar range by binding in a similar binding pocket to that occupied by GABA. Embarking upon in silico-driven screening to develop synthetic openers of Kv7 and Kv1 channels, we were able to discover potent channel openers originally derived from glycine.
a. Manville RW, Abbott GW. (2018) Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels. Molecular Pharmacology. 94(4):1155-1163. PMC6108572
b. Manville RW, Abbott GW. (2019) In silico re-engineering of a neurotransmitter to activate KCNQ potassium channels in an isoform-specific manner. Communications Biology 2:401. eCollection 2019. PMC6825221
c. Manville RW, Abbott GW. (2020) Isoform-Selective KCNA1 Potassium Channel Openers Built from Glycine. J Pharmacol Exp Ther. 373(3):391-401. PMID: 32217768 PMC7228494 (COVER ARTICLE)
d. Manville RW, Papanikolaou M, Abbott GW. (2020) M-Channel Activation Contributes to the Anticonvulsant Action of the Ketone Body ß-Hydroxybutyrate. J Pharmacol Exp Ther. 372(2):148-156. (COVER ARTICLE) PMC6994816
(iv) Channel-transporter interactions
We discovered physical and functional interactions between Kv7 potassium channels and sodium-coupled solute transporters, defining a previously unknown class of macromolecular signaling complexes. These complexes are influential in epithelial and excitable cell biology; their dysfunction underlies syndromes we have demonstrated in knockout mice-the first report of a physical interaction between a K+ channel and a transporter – and ongoing studies in my lab have uncovered still more. This work helped to bridge the fields of ion channels and solute transporters. Based on existing evidence from us and now other labs, I believe this type of complex is prevalent in biology. The work also opens up potential novel therapeutic avenues, as we showed that transporters can be modulated by highly channel–specific small molecules that target their partner ion channels.
a. Abbott GW* et al.,(2014) KCNQ1, KCNE2, and Na+-Coupled Solute Transporters Form Reciprocally Regulating Complexes that Affect Neuronal Excitability. Science Signaling 4 March 2014: ra22 *First and corresponding author. PMC4063528
b. Neverisky, D.L. Abbott, G.W. (2017) KCNQ-SMIT complex formation facilitates ion channel-solute transporter crosstalk. FASEB Journal 31(7):2828-2838. PMC5472404
c. Manville, R.W., Neverisky, D. L., Abbott, G.W. (2017) SMIT1 modifies KCNQ potassium channel ion selectivity, gating and pharmacology by physical interaction with the pore. Biophysical Journal 113(3)613-626. PMC5550323. Highlighted in New and Notable Editorial
d. Manville, R.W., Abbott, G.W. (2020) Potassium channels act as chemosensors for solute transporters. Communications Biology. 3(1):90. PMC7048750.
(v) The KCNE gene family
When a post-doc in the Goldstein laboratory, I was first author on two articles in which we reported discovery of the majority of the KCNE gene family of potassium channel regulatory subunits (that had existed as an orphan subunit, KCNE1, since 1988) and showed links between KCNE mutations and inherited human disease. These articles contributed heavily to a new realization of the necessity of heteromeric ion channels, and the KCNEs are now the most highly studied voltage-gated ion channel regulatory subunits. More recently, I found that KCNE3 & 4 are extended by novel exon 1 coding regions; the new segments alter function and suggest novel Kv channel regulation by KCNE gene splicing. My lab has also utilized knockout mouse models to discover that the Kv7.1-KCNE2 potassium channel is essential for several epithelial cell systems in vivo, including the gastric and choroid plexus epithelia. Most strikingly, we discovered the first role for a cation channel in thyroid gland epithelial cells. This work provided the first evidence that a cation channel could be required for the normal function of a sodium-coupled solute transporter, which led to our other work on channel-transporter interactions (see above). Our original paper on Kv7.1-KCNE2 in the thyroid was also the first to describe how disruption of genes linked to lethal human cardiac arrhythmias can impair cardiac function and structure by mechanisms other than directly causing electrical malfunction in cardiac myocytes. We also found that Kcne2 deletion impairs milk ejection and neonatal development, and the paper was highlighted as Mechanism of the Year in the Yearbook of Pediatric Endocrinology, 2010. We next helped to better understand NIS inhibition by the pollutant, perchlorate.
a. Abbott, G.W. et al., (1999) MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97 175-187 PMID: 10219239 this article has >1780 citations.
b. Abbott, G.W. et al., (2001) MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 104 217-31 PMID: 11207363
c. Roepke TK, King EC, Reyna-Neyra A, Paroder M, Purtell K, Koba W, Fine E, Lerner DJ, Carrasco N, Abbott GW. (2009) Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis. Nature Medicine 15(10):1186-94. PMC2790327. Highlighted as Mechanism of the Year in the Yearbook of Pediatric Endocrinology, 2010; Faculty of 1000 Prime recommended
d. Llorente-Esteban A, Manville RW, Reyna-Neyra A, Abbott GW, Amzel LM, Carrasco N. (2020) Allosteric regulation of mammalian Na+/I- symporter activity by perchlorate. Nature Structure Mol Biol. 27(6):533-539. PMID: 32451489 PMC10158964