- Ion channels in cancer
Ion channels are vital for almost all cellular processes and functions. In case of aberrant expression or malfunctioning of ion channels, ion fluxes generated by these channels cause global or local changes in cellular functions by, for instance, altering calcium signaling, cell volume, mechanosensation, membrane potential, and microenvironment. These changes not only contribute to the malignant transformation and but also are associated with chemotherapeutic resistance of cancer cells (1-2). Therefore, identifying ion channels involved in cancerogenesis, metastasis, and drug resistance, and elucidating the underlying molecular mechanisms is a timely and emerging field of research.
Our focus is on understanding the role of ion channels in carcinogenesis and metastasis. In particular, we are interested in elucidating the role of ion channels in the cellular transition to a metastatic form and related bilateral intercellular communication. We are currently performing preliminary proof-of-concept research on neuroblastoma and prostate cancer cells and their extracellular vesicles.
(1) Physiol Rev 98: 559-621, 2018; (2) Cancers 11: 376-408, 2019
- Ion channels in the nervous system
- Molecular mechanism of cAMP-induced synaptic plasticity
Financial support:
* NWO-ALW Open Programme (2019)
One of the most crucial features of the brain, known as the synaptic plasticity, is its ability to adapt continually to changes in the environment by modifying the strength and efficacy of synaptic connections between neurons. At the molecular level, specific membrane proteins called AMPA receptors (AMPARs) are crucial for various forms of synaptic plasticity. These are ligand-gated cation channels present at most excitatory synapsis. They mediate fast signal transmission between neurons in response to the presynaptic release of the neurotransmitter glutamate. A change in the number and/or function of AMPARs is a core feature of synaptic plasticity and is fundamental in learning and memory. Recently, a novel mechanism of synaptic plasticity is reported (1,2), which is mediated by cAMP-dependent changes on single-channel properties of GluA3 in GluA2/3 receptors leading to increased conductance, long-term potentiation, and motor learning in Purkinje cells. Our long-term goal is to dissect molecular mechanisms modulating channel properties of GluA3-containing AMPA receptors (3).
(1) Neuron 93: 409-424, 2017
(2) eLife 6: e25462, 2017
(3) Kennis in Zicht article
- Voltage-gated potassium channel Kv4.3
Voltage-gated potassium channel Kv4.3 of Purkinje neurons is involved in the so-called “A-type current” that activates and inactivates very fast at the initial stage of the action potential. Kv4.3 is involved in controlling the electrical activity of Purkinje neurons, for governing the fine-tuned motor coordination of the body. Patients carrying mutated forms of Kv4.3 lose their Purkinje cells and cerebellar tissue, in time, and cannot control their voluntary movements anymore. The mechanism leading to this miscommunication is yet not fully known.
The altered electrical activity of cerebellar neurons precedes the ultimate Purkinje neuron death, and the correction of abnormal electrical activity limits the development of motor symptoms and prevent Purkinje neuron atrophy. Therefore, our working hypothesis is that Kv4.3 mutations cause Purkinje neuron death by changing the voltage-sensitivity, magnitude, and/or the kinetics of the A-type current, thereby altering the action potential output of Purkinje neurons.
To test our hypothesis, we followed a bottom-up approach and collaborated with Prof. Verbeek on the hereditary and de novo mutants. After heterologous expression of human Kv4.3 in Chinese hamster ovary cells in the presence and absence of an auxiliary protein KChIP, we determined the main changes on the single-channel and ensemble properties the Kv4.3 mutants as compared to the wild-type channel. We related the experimental results to the underlying structural mechanisms by using a homology model of the channel and full atomistic molecular dynamics simulation performed by the groups of Prof. Brancato. Three publications are in preparation.