Dr. Huanghe Yang is the head researcher on the IETF’s funded research study for 2017, “Elucidating the Roles of the Ca2+-activated Ion Channels in Essential Tremor.” This blog from him shows how detail-oriented this research study is and his depth of knowledge in this subject area.
By Huanghe Yang, PhD
Duke University School of Medicine
The exact pathogenesis mechanism (or manner of development) of essential tremor (ET) is still unclear. We do know, however, abnormal neuronal firing directly causes the ET phenotypes (characteristics or traits). Thus, various means to correct the abnormal neuronal firing in the key brain regions for tremor genesis have been developed to improve the life quality of ET patients.
In order to develop more effective ET therapy, we need to have better understanding on how neuronal firing goes awry in ET. Neurons are ‘excitable’, meaning that they can fire electrical signals called ‘action potentials’. These electrical signals can be rapidly propagated from one end of a neuron to the another end, thereby enabling fast information relay from one neuron to its targeting neurons. When the electrical signals fire at abnormal frequency, serious neurological disease will occur, including but not limited to ET, ataxia and epilepsy.
Neuronal firing is controlled by a group of electrogenic proteins residing on cell surface, called ion channels. Ion channels, like dams of water reservoirs, control charged ions to flux across cell membranes. When open, they quickly allow ions to go down their gradients, resulting in change of membrane voltage, thus generating electric signal. Ion channels, thus, are a class of essential proteins that control a cell’s electrical activities. Thus far, many ion channels have been identified to be associated with various neurological disorders.
Voltage-gated calcium channels (VGCCs) are absolutely required for all neurons. Increase of membrane voltage will open the VGCCs and allow calcium ions to flush into a neuron. This calcium influx will not only further alter membrane voltage, but also quickly increase intracellular calcium concentration. During evolution, calcium has been selected as a universal and master regulator of numerous cellular processes. Therefore, the activities of the VGCCs need to be tightly regulated. Too much or too little activities of the VGCCs will lead to severe diseases such as cardiac arrhythmias, epilepsy, ataxia and migraine.
The exact roles of the VGCCs in human ET pathogenesis have not been clearly dissected. Yet interestingly, the involvement of VGCCs in tremorgenesis in rodent models has long been established. In fact, in a routine rodent ET model, a VGCC in the inferior olivary (IO) nucleus is believed to be the major target of harmaline, a psychoactive alkaloid drug from hallucinogenic plants. Injection of harmaline into rodents quickly and reliably activates the VGCCs in IO neurons, resulting in severe tremor.
We recently discovered that in addition to the VGCCs, IO neurons also express various types of calcium-activated ion channels, including calcium-activated chloride channels (CaCC) and calcium-activated large conductance potassium (BK) channels and calcium-activated small conductance potassium (SK) channels. These calcium-activated ion channels stay in close proximity to the VGCCs and form a highly dynamic and balanced feedback network with the VGCCs. Once calcium influxes through the VGCCs, the calcium-activated channels will quickly respond; and the subsequent chloride and potassium flux through these channels will quickly change membrane voltage and in turn, shut down VGCCs. Indeed, when we genetically deleted the CaCC in IO neurons, the mice had severe defect on learning new motor tasks.
With the generous support from International Essential Tremor Foundation, we have been further exploring the dedicated interactions between the VGCCs and the calcium activated ion channels in the IO, one of the key brain region for ET tremorgenesis. We have discovered that there are multiple types of VGCCs in IO neurons, which have long been believed only express the P/Q type and T type VGCCs. We are currently dissecting the contributions of each type of VGCCs and their downstream calcium-activated ion channels in mouse tremorgenesis. Our findings will help understand the basic mechanism of tremorgenesis.
We aim to translate our findings into novel therapeutic interventions to alleviate tremor symptoms and lessen functional disability associated with ET.
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July is a time with the IETF draws awareness to its many research initiatives: funding research grants, advocating for more research on essential tremor, recruiting for research studies, and more. Your generosity is the reason the IETF is able to carry out these initiatives and work toward improving the quality of life for every generation living with essential tremor. Help us keep hope alive. Donate today.