Abstract

The presynaptic nerve terminal is a complex structure containing many proteins that control neurotransmitter release. Identifying the various regulatory proteins and elucidating their mechanisms of action are critical to understanding how the presynaptic terminal regulates neurotransmitter release rapidly and dynamically. The BK channel, a high-conductance and voltage/calcium-gated potassium channel, colocalizes with voltage-gated calcium channels at the presynaptic terminal and serves as a powerful negative regulator of neurotransmitter release. To identify novel regulators of neurotransmitter release, a genetic screen was performed to isolate mutants suppressing a lethargic phenotype caused by a hyperactive BK channel in C. elegans. Mutants of bkip-2 and bkip-4 (bkip for BK channel Interacting Protein) were isolated. BKIP-2 and BKIP-4 both have mammalian homologues with unknown functions in the brain. Preliminary studies suggest that BKIP-2 is required for BK channel function in neurons whereas BKIP-4 regulates neurotransmitter release through a mechanism that appears to be independent of the BK channel.
The specific aims of this proposal are: (1) test the hypothesis that BKIP-4 regulates neurotransmitter release through controlling presynaptic Ca2+ concentration; (2) determine whether BKIP- 4 mutation alters neural anatomy, and whether BKIP-4 function is conserved in mammals; and (3) determine how BKIP-2 regulates the function of presynaptic BK channels. The long-term goals are to answer the important questions how various presynaptic proteins interact to shape neural circuits dynamically and why mutations of these proteins may cause diverse human diseases.

Public Health Relevance

This project is to investigate the physiological roles and molecular mechanisms of action of two novel regulators of neurotransmitter release. Such knowledge is critical to understanding how presynaptic proteins interact to shape neural circuits rapidly and dynamically, and how their deficiencies may cause various human diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085927-10
Application #
9688876
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Kim, Douglas S
Project Start
2009-04-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2021-04-30
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
University of Connecticut
Department
Neurosciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030

  Publications

Liu, Ping; Wang, Sijie Jason; Wang, Zhao-Wen et al. (2018) HRPU-2, a Homolog of Mammalian hnRNP U, Regulates Synaptic Transmission by Controlling the Expression of SLO-2 Potassium Channel in Caenorhabditis elegans. J Neurosci 38:1073-1084
Hawk, Josh D; Calvo, Ana C; Liu, Ping et al. (2018) Integration of Plasticity Mechanisms within a Single Sensory Neuron of C. elegans Actuates a Memory. Neuron 97:356-367.e4
Liu, Ping; Chen, Bojun; Mailler, Roger et al. (2017) Antidromic-rectifying gap junctions amplify chemical transmission at functionally mixed electrical-chemical synapses. Nat Commun 8:14818
Niu, Long-Gang; Liu, Ping; Shui, Yuan et al. (2017) BKIP-1, an auxiliary subunit critical to SLO-1 function, inhibits SLO-2 potassium channel in vivo. Sci Rep 7:17843
Chen, Bojun; Liu, Ping; Hujber, Edward J et al. (2017) AIP limits neurotransmitter release by inhibiting calcium bursts from the ryanodine receptor. Nat Commun 8:1380
Liu, Ping; Chen, Bojun; Wang, Zhao-Wen (2014) SLO-2 potassium channel is an important regulator of neurotransmitter release in Caenorhabditis elegans. Nat Commun 5:5155
Liu, Ping; Chen, Bojun; Wang, Zhao-Wen (2013) Postsynaptic current bursts instruct action potential firing at a graded synapse. Nat Commun 4:1911
Wang, Sijie Jason; Wang, Zhao-Wen (2013) Track-a-worm, an open-source system for quantitative assessment of C. elegans locomotory and bending behavior. PLoS One 8:e69653
Liu, Ping; Chen, Bojun; Altun, Zeynep F et al. (2013) Six innexins contribute to electrical coupling of C. elegans body-wall muscle. PLoS One 8:e76877
Zhan, Haiying; Moore, Craig S; Chen, Bojun et al. (2012) Stomatin inhibits pannexin-1-mediated whole-cell currents by interacting with its carboxyl terminal. PLoS One 7:e39489

Showing the most recent 10 out of 16 publications