Add to the readme to create a well cited and reasoned case for the ideal set of ion channels that should be in the muscle model
slarson opened this issue · 8 comments
Currently the ion channels we have in the model are known to be simplifications. We'll close this issue when we have found some references that tell us what channels should be there and agreed to a fixed list.
From @a-palyanov 's manuscript on ion channels in Pharyngeal muscles, the list would be:
- EGL-19 L-Type Ca+
- CCA-1 T-Type Ca+
- Kv-type EXP-2 K+
@a-palyanov is there a leak channel at all in your model?
Note that we have the beginnings of an EGL-19 model generating function here: https://github.com/openworm/ChannelWorm/blob/master/channelworm/fitter/examples/EGL-19-2.py
@VahidGh What are the prospects for getting CCA-1 and EXP-2 via ChannelWorm? I will also share @a-palyanov's manuscript with you.
@slarson, Regarding determining the set of ion channels in muscle cells, what could be inferred from different studies is that there are different ion channels being expressed in different muscle cells (body wall, pharynx, egg-lying muscles, etc.). Current list could be a candidate for different muscle cells according to current studies:
- For body wall muscles, EGL-19 (plus UNC-36 and CCB1 subunits) , SLO-2, SHK-1, SHL-1, and possibly SLO-1, and CCA-1:
Ping Liu, et.al, 2015:
"In C. elegans body-wall muscle, SLO-2 conducts approximately 70% of the total delayed outward current; and slo-2 loss-of-function (lf) mutation results in a more depolarized resting membrane potential, a wider action potential waveform, and a smaller amplitude of after hyperpolarization, suggesting that SLO-2 plays important roles in controlling muscle function (25). Although SLO-2 is also expressed in the nervous system (23, 26), its physiological roles in neurons are unknown.
Previous studies show that three voltage-gated K+ channels are important to outward current in C. elegans body-wall muscle cells, including SLO-2, SHK-1 (Shaker or KV1) and SHL-1 (Shal or KV4), with SLO-2 and SHK-1 conducting delayed outward current and SHL-1 conducting a fast and transient outward current (25, 34, 35)."
Viviane Lainé, et.al, 2011:
"We show that EGL-19 is the only α1 subunit that carries calcium currents in muscle cells. We then demonstrate that the α2/δ subunit UNC-36 modulates the voltage dependence, the activation kinetics, and the conductance of calcium currents, whereas another α2/δ subunit TAG-180 has no effect. Finally, we characterize mutants of the two β subunits, CCB-1 and CCB-2. CCB-1 is necessary for viability, and voltage-dependent calcium currents are abolished in the absence of CCB-1 whereas CCB-2 does not affect currents. Altogether these results show that EGL-19, UNC-36, and CCB-1 underlie voltage-dependent calcium currents in C. elegans striated muscle."
Ping Liu, et.al, 2010:
"we show that muscle APs depend on Ca2+ entry through the L-type Ca2+ channel EGL-19 with a contribution from the T-type Ca2+ channel CCA-1. Both the Shaker K+ channel SHK-1 and the Ca2+/Cl−-gated K+ channel SLO-2 play important roles in controlling the speed of membrane repolarization, the amplitude of after hyperpolarization (AHP) and the pattern of AP firing; SLO-2 is also important in setting the resting membrane potential. Finally, AP-elicited elevations of [Ca2+]i require both EGL-19 and the ryanodine receptor UNC-68.
EGL-19 and, possibly, CCA-1 are expressed in body-wall muscle cells (Lee et al. 1997; Steger et al. 2005), and EGL-19 is a major carrier of inward current, playing an important role in generating the reported graded APs in body-wall muscle cells (Jospin et al. 2002). The other three channels (UNC-2, NCA-1 and NCA-2) are primarily expressed in the nervous system with muscle expression detected only at the worm tail for NCA-2 (http://www.wormbase.org). In addition, C. elegans body-wall muscle cells express a variety of K+ channels (Kunkel et al. 2000; Yuan et al. 2000; Salkoff et al. 2001; Wang et al. 2001; Salkoff et al. 2005) and a RyR, which is encoded by the unc-68 gene (Maryon et al. 1998). Three of the identified K+ channels, including SHL-1 (Shal or Kv4 type), SHK-1 (Shaker or Kv1 type) and SLO-2 (Ca2+- and Cl−-gated) appear to be the predominant carriers of outward currents (Santi et al. 2003; Fawcett et al. 2006).
In the present study, we determined the electrical properties of APs in C. elegans body-wall muscle cells, analysed the role of specific ion channel gene products in generating and shaping APs, and determined how APs lead to an elevation of [Ca2+]i and muscle contraction. We found that body-wall muscle APs are all-or-none events rather than graded depolarizations as previously reported, and that unlike those of mammalian skeletal muscle fibres, body-wall muscle APs occur in the absence of neural input. We also report that SHK-1 and SLO-2 K+ channels contribute to body-wall muscle APs, and that trains of APs are associated with elevations of [Ca2+]i, which required the functions of both the EGL-19 Ca2+ channel and the UNC-68 ryanodine receptor channel."
Carre-Pierrat M, et.al, 2006:
"Here, we report that SLO-1 also has a critical role in muscles. Inactivation of the slo-1 gene in muscles leads to phenotypes similar to those caused by mutations of the dystrophin homologue dys-1. Notably, slo-1 mutations result in a progressive muscle degeneration when put into a sensitized genetic background. slo-1 localization was observed by gfp reporter gene in both the M-line and the dense bodies (Z line) of the C. elegans body-wall muscles. Using the inside-out configuration of the patch clamp technique on body-wall muscle cells of acutely dissected wild-type worms, we characterized a Ca2C-activated KC channel that was identified unambiguously as SLO-1. Since neither the abundance nor the conductance of SLO-1 was changed significantly in dys-1 mutants compared to wild-type animals, it is likely that the inactivation of dys-1 causes a misregulation of SLO-1. All in all, these results indicate that SLO-1 function in C. elegans muscles is related to the dystrophin homologue DYS-1."
C. M. Santi, et.al, 2003:
"We found that under physiological conditions, outward current is dominated by the products of only two genes, Shaker (Kv1) and Shal (Kv4), both expressing voltage-dependent potassium channels. Other channels may be held in reserve to respond to particular circumstances. Because GFP-promoter experiments indicated that slo-2 expression is prominent, we created a deletion mutant to identify the SLO-2 current in vivo. In both whole-cell and single-channel modes, in vivo SLO-2 channels were active only when intracellular Ca2+ and Cl- were raised above normal physiological conditions, as occurs during hypoxia."
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Pharynx muscle; CCA-1, EGL-19, and EXP-2:
Boris Shtonda and Leon Avery, 2006:
"We show that CCA-1 exhibits T-type calcium channel properties: activation at −40 mV and rapid inactivation. Our results suggest that CCA-1’s role is to accelerate the action potential upstroke in the pharyngeal muscle in response to excitatory inputs. Similarly to other L-type channels, EGL-19 activates at high voltages and inactivates slowly; thus it may maintain the plateau phase of the action potential. EXP-2 is a potassium channel of the kV family that shows inward rectifier properties when expressed in Xenopus laevis oocytes. We show that endogenous EXP-2 is not a true inward rectifier – it conducts large outward currents at potentials up to +20 mV and is therefore well suited to trigger rapid repolarization at the end of the action potential plateau phase." -
Egg-lying muscle; EGL-36:
Daniel A Elkes, et.al, 1997:
"Here we show that the egl-36 gene encodes a C. elegans Shaw-type potassium channel. We provide genetic, molecular, and biophysical evidence that EGL-36 channels regulate the excitability of the egg-laying and defecation muscles in vivo."
As for using ChannelWorm to build models for above mentioned channels, this could be a great case study to compare/validate results from different studies and methods.
We have data for CCA-1, EGL-19, and EXP-2 from Xenopus Oocytes and C. elegans muscle cells. Would be interesting to build models for these channels and compare results with the interesting work by @a-palyanov.
@VahidGh Great re-summary!
@pgleeson Does this look complete to you? Can we use this as the list? Would be great to set this down for now.
@a-palyanov I'm interested if you saw references to the other channels that @VahidGh mentioned in the pharyngeal work you did?
"Is there a leak channel at all in your model?"
Yes, there is a leak channel, for which the built-in NEURON mechanism "insert pas" is used.
There are two parameters which influence the properties of the passive channels: g_pas (S/cm^2) and e_pas (mV). The used values are listed in Table 1 of the manuscript.
@VahidGh thanks for this nice summary! That's certainly the detail we need to hammer down the channels. I'll look again at the references for BoyleCohen and see what they are and look initially at @a-palyanov's channels to see how easy it would be to get them into NeuroML for comparison.
Maya T. Kunkel, et al, 2000
"Within the Caenorhabditis elegans genome there exist at least 42 genes encoding TWK (two-P domain K+) channels, potassium channel subunits that contain two pore regions and four transmembrane domains. We now report the first functional characterization of a TWK channel from C. elegans. Although potassium channels have been reported to be activated by a variety of factors, TWK-18 currents increase dramatically with increases in temperature.
Expression of GFP driven by the twk-18 promoter indicates expression limited to body wall muscle.
In addition to twk-18 there are at least three other TWK family members expressed in the body wall muscle of C. elegans (A. Butler, G. Paz-y-Mino C., and L. Salkoff, unpublished observations)."
There are more channels for sure but I guess that the most important channels have already been mentioned.
This paper is also relevant: searchdl.org/index.php/conference/downloadPDF/1102.
Modeling Action Potentials of Body Wall Muscles in C. elegans: A Biologically Founded Computational Approach
Callen Johnson and Roger Mailler
Channels implemented in NeuroML by @lungd here: https://github.com/openworm/CElegansNeuroML/blob/master/CElegans/pythonScripts/c302/custom_muscle_components.xml