Nearly four decades have passed since I first walked through the doors of Queen’s University Belfast in September 1986 to study Physiology as an undergraduate. Since then I’ve been fortunate to build a career alongside outstanding colleagues, united by a shared curiosity about how smooth muscle generates and shapes electrical signals to drive physiological function.

A central theme of the research in our Smooth Muscle Research Centre has been the characterization of ion channels and their role in regulating the electrical and mechanical activity of lymphatic^1-4, lower urinary tract^5-15 and airway smooth muscles^16-19. Earlier in my career, this led to a significant technical and scientific challenge: the study of lymphatic smooth muscle. At the time, few scientists had successfully recorded electrical activity from freshly isolated lymphatic smooth muscle cells. Nevertheless, we established reliable cell isolation procedures and managed to utilise patch clamping to characterise the major ionic currents in lymphatic smooth muscle^1-4 and lay the foundations for future work on how electrical activity governed lymphatic contractility.

Around the same time, we demonstrated for the first time that interstitial cells of Cajal (ICC), well established as pacemaker cells in the gastrointestinal tract, were also present in non-gastrointestinal smooth muscles^6-10. This finding expanded the conceptual framework of how smooth muscle contractile activity was generated and coordinated. Subsequent work, supported by NIH funding, explored the electrophysiological properties of these cells and their modulation by neurotransmitters, helping to establish ICC and related cell types as key intermediaries in smooth muscle signalling across multiple organ systems.

We were also fortunate to be actively engaged in translational collaborations with industry. In the early 2000s, in partnership with Andor Technology, we were glad to help in the development of electron multiplying CCD (EMCCD) cameras for biological imaging^20-22. Originally designed for astronomy, these sensors transformed the ability to detect low Ca²⁺ signals in single cells and tissues, overcoming limitations of earlier imaging systems. Since their commercial introduction in 2003, EMCCD technology quickly became a cornerstone of live-cell imaging, illustrating the impact of cross-disciplinary innovation.

More recently our work has focused on the development of novel ion channel modulators and how they interact with their targets at the molecular level. Through the synthesis and characterization of a novel family of GoSlo-SR compounds we have generated potent ion channel modulators^23-25, determined their molecular mechanism of action²⁶ and patented the most promising structures²⁷.

Complementing this in 2020, we identified the LINGO family of proteins as previously unrecognized regulatory subunits of BK channels^28-31. Given the upregulation of LINGO proteins in Parkinson’s disease²⁸, we have proposed a mechanistic link between LINGO-associated BK channel dysfunction and the emergence of Parkinsonian tremor, opening new avenues for therapeutic intervention. In this invited talk, I’ll focus on some of our more recent research in which we’ve examined the molecular mechanisms underlying BK channel modulation by these novel regulatory LINGO subunits.