Society of
General physiologists

Emeritus Professor David A. Brown, FRS (1936-2023)

David Brown died on October 21, 2023, at the age of 87. Neuropharmacologist, dear mentor to many, and academic and scientific leader, David early on discovered peripheral GABA receptors and GABA transporters in glia. But then, together with Paul Adams, he discovered, described, and named a new ionic current, the M-current, of the cell bodies of sympathetic ganglia in a series of landmark papers beginning in 1980 (Brown and Adams, 1980). This became the primary subject of the rest of his career and his landmark scientific work. In neurons, the M-current is a potassium current that is active near rest and turned off by the Muscarinic action of acetylcholine on M₁ receptors, increasing cellular excitability.  Of his interests, David had written for his lab webpage, “My work concerns the regulation of ionic currents involved in controlling nerve excitability, particularly through changes in intracellular mediators such as calcium and protein kinase C produced by acetylcholine.”  Later it was realized that the M-current channels are dependent on the inositol phospholipid PI(4,5)P₂ in the membrane (Suh and Hille, 2002; Zhang et al., 2003), and the Brown lab became one of the leaders in validating and expanding the hypothesis that receptor-mediated depletion of PI(4,5)P₂ is a key factor underlying the inhibition of KCNQ channels.

To David’s modestly confessed delight, the scientific significance of the M-current grew enormously in the 4 decades after his 1980 discovery. Suppression of M-current became recognized through David’s work and that of numerous other labs as a mechanism that increased the excitability and arousal of many kinds of central neurons in response to a broad range of agonists that coupled to the G protein G_q. Receptor-activated G_q turned on phospholipase C, whose most important consequence was eventually recognized as the depletion of PI(4,5)P₂. When, only after several decades, the underlying pore-forming subunits of M-current were finally cloned (Wang et al., 1998), they formed a larger family of KCNQ or K_V7 genes that were expressed even more widely that realized. One of them, KCNQ1, underlies the repolarizing I_Ks current of the cardiac action potential and also is a repolarizing brake on insulin secretion from pancreatic β cells. KCNQ1 had been cloned as a deletion that caused long QT syndrome and cardiac arrest (Wang et al., 1996). On the other hand, opening of KCNQ5 channels in vascular smooth muscle relaxes vascular tone. Today a search on the PubMed data base for the channels that David Brown discovered 43 years ago yields over 5,000 papers.

My lab knew David internationally and at Society for Neuroscience and other meetings as a kind, intense, energetic, sharp, prolific, inquisitive, and deeply-informed scientist, colleague, and competitor. He was keen to share and hear about the latest on what eventually became KCNQ channels, always generous with information, and a delight to spend time with. We might all gather on the floor around unrolled posters for a vigorous discussion. We learned so much from David. He was a fount of all knowledge cholinergic. David’s voice was strong and conversation was easy with many chuckles, laughs, and quiet humor. His informative Emails were filled with historical and current references complete with PubMed IDs--and humor. For example, in one he apologizes for a delay “over an extended public ‘bank-holiday’ weekend,“ saying, “Trust the UK to have holidays for banks whereas other countries have holidays for saints or heroes.”

David graduated from University College London with a BSc degree in Chemistry, Zoology and Physiology, followed by Special Physiology, and later obtained a PhD in pharmacology from St. Bartholomew's Hospital Medical College London University (1961). He held positions in pharmacology successively at St. Barts, at the School of Pharmacy London University, and at UCL. He served as Head of Pharmacology at the School of Pharmacy (1979-1987) and at UCL for 15 years (1987-2002) and was editor-in-chief of the British Journal of Pharmacology and on the editorial boards of many other journals.  Even years into his “retirement” he wrote a marvelous review “Acetylcholine and cholinergic receptors” (Brown, 2019) that I commend to anyone seeking a very readable overview and historical perspective of a complex and exciting field. David attracted high-quality collaborators and trainees, many of whom continue in his footsteps. They hold him in highest regard and treasure him as their career advisor. Their contributions added to the excellence of his papers. The messages from his collaborators and colleagues use such words as “sage,” “caring and supportive,” “a creative atmosphere in the lab with bright researchers,” “one of a kind,” “a huge figure for many of us,” a “wise and charismatic colleague,” a “consummate English gentleman.” 

David Brown was a valued friend and colleague. I will miss him. I credit him with starting the subject that dominated the second half of my own career and opened a major field in basic and translational neurobiology.

Bertil Hille, PhD, NAS, NAM, Professor Emeritus

University of Washington School of Medicine 

References

Brown DA. (2019) Acetylcholine and cholinergic receptors. Brain Neurosci Adv. 3:2398212818820506. doi: 10.1177/2398212818820506. 2019. PMID: 32166177

Brown DA, Adams PR. (1980) Muscarinic suppression of a novel voltage-sensitive K⁺ current in a vertebrate neurone. Nature 283:673–676. doi: 10.1038/283673a0.PMID: 6965523

Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, ShenJ, Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Toubin JA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT. (1996) Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet . 12:17-23. doi: 10.1038/ng0196-17. PMID: 8528244

Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, Cohen IS, Dixon JE, McKinnon D. (1998) KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M channel. Science 282:1890–1893. doi: 10.1126/science.282.5395.1890. PMID: 9836639

Zhang H, Craciun LC, Mirshahi T, Rohács T, Lopes CM, Jin T, Logothetis DE. (2003) PIP₂ activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron. 37:963-75. doi: 10.1016/s0896-6273(03)00125-9. PMID: 12670425

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