BK channels are almost ubiquitously expressed and perform many important physiological functions. Dysfunction of the channel causes a variety of diseases, including epilepsy, progressive hearing loss, cerebellar ataxia, and hypertension. The function of BK channels depends on proper subcellular localization and interactions with auxiliary or regulatory proteins. However, the molecular basis of BK channel subcellular localization is unknown and only limited knowledge exists about BK channel auxiliary/regulatory proteins. The powerful molecular genetics of C. elegans is explored to identify proteins important to BK channel function or subcellular localization. In preliminary studies, mutants of three genes (named as bkip-1, bkip-2 and bkip-3) were isolated as suppressors of a lethargic phenotype caused by expressing a gain-of-function (gf) isoform of SLO-1, the C. elegans BK channel. Phenotypes of these mutants included increased neurotransmitter release (bkip-1) and SLO-1 mislocalization (bkip-2 and bkip-3). bkip-1 and bkip-2 were found to encode novel BK channel- interacting proteins whereas bkip-3 remains to be identified. BKIP-1 showed several effects on SLO-1 functional properties when analyzed in a heterologous expression system. This proposal is to test the hypotheses that the three BKIPs are important to SLO-1 function and/or subcellular localization in vivo and that there are other functionally related proteins in C. elegans.
The specific aims of this proposal are: (1) determine how BKIP-1 regulates SLO-1 function;(2) determine how BKIP-2 and BKIP-3 control SLO-1 subcellular localization and/or function, and (3) isolate and identify additional mutants that suppress the lethargic phenotype caused by SLO-1(gf), which will be analyzed in future studies. The long-term goal is to elucidate the molecular basis of BK channel function and subcellular localization.

Public Health Relevance

Mutations of the BK channel cause a variety of diseases, including epilepsy, hypertension, progressive hearing loss, cerebellar ataxia, overactive bladder, penile erectile dysfunction, impaired renal glomerular filtration and K+ excretion, and paroxysmal dyskinesia. The proposed research program may identify novel proteins that are important to BK channel function and/or subcellular localization in vivo. Such information is potentially of great value to understanding the molecular bases of BK channel-related diseases, and to identifying candidate pharmacological targets for the treatment and management of these diseases.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Asanuma, Chiiko
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University of Connecticut
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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

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