Copyright ? 2007 by the Genetics Society of America
A Specific Subset of Transient Receptor Potential Vanilloid-Type Channel
Subunits in Caenorhabditis elegans Endocrine Cells Function as Mixed
Heteromers to Promote Neurotransmitter Release
Antony M. Jose,1I. Amy Bany,2Daniel L. Chase and Michael R. Koelle3
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520
Manuscript received September 5, 2006
Accepted for publication October 2, 2006
Transient receptor potential (TRP) channel subunits form homotetramers that function in sensory
transduction. Heteromeric channels also form, but their physiological subunit compositions and functions
are largely unknown. We found a dominant-negative mutant of the C. elegans TRPV (vanilloid-type) subunit
OCR-2 that apparently incorporates into and inactivates OCR-2 homomers as well as heteromers with the
TRPV subunits OCR-1 and -4, resulting in a premature egg-laying defect. This defect is reproduced by
knocking out all three OCR genes, but not by any single knockout. Thus a mixture of redundant
heteromeric channels prevents premature egg laying. These channels, as well as the G-protein Gao,
function in neuroendocrine cells to promote release of neurotransmitters that block egg laying until eggs
filling the uterus deform the neuroendocrine cells. The TRPV channel OSM-9, previously suggested to be
an obligate heteromeric partner of OCR-2 in sensory neurons, is expressed in the neuroendocrine cells but
has no detectable role in egg laying. Our results identify a specific set of heteromeric TRPV channels that
redundantly regulate neuroendocrine function and show that a subunit combination that functions in
sensory neurons is also present in neuroendocrine cells but has no detectable function in these cells.
transient receptor potential (TRP) family to translate
sensory stimuli into electrical signals (Montell 2005).
These tetrameric cation channels can be homomers of
identical subunits or heteromers of two or more dif-
ferent subunits. TRP channels have been widely studied
by overexpressing homomeric channels in cultured
cells or Xenopus oocytes. However, it remains unclear
to what extent native TRP channels function as homo-
mers vs. as heteromers, and what rules might govern
the association of the various TRP subunits into func-
Genetic studies can potentially reveal the physiolog-
ical functions of TRP channels and whether homomers
or heteromers carry out these functions. Four of the six
mammalian TRPV (vanilloid-type) subunits have been
knocked out in mice. TRPV1 knockouts have defects in
responding to noxious stimuli (Caterina et al. 2000;
Davis et al. 2000), in osmosensation by neurons of the
supraoptic nucleus (Naeini et al. 2006), and in mecha-
OUCH, hearing, taste, vision, smell, and temper-
ature sensation may all rely on channels of the
nosensation by urothelial cells (Birder et al. 2002).
TRPV3 knockouts have a defect in thermosensation by
the skin (Moqrich et al. 2005). TRPV4 knockouts have
defects in sensing systemic osmotic pressure (Liedtke
et al. 2000). Finally, TRPV5 knockouts have renal Ca21-
handling defects (Hoenderop et al. 2003a). It remains
unclear whether these defects are due to loss of ho-
momeric channels or due to the knockouts disrupting
a more complex mixture of heteromers. In addition,
TRPV subunits are expressed in overlapping patterns
with other TRP subunits in tissues such as the inner ear,
brain, and heart (Montell 2005), where their func-
tions have not been revealed by the knockout studies.
One reason for this could be that, as in Drosophila
vision, coexpressed TRP subunits may compensate
for the lack of one TRP subunit in single knockouts
(Niemeyer et al. 1996; Reuss et al. 1997).
The functions of coexpressed TRPV subunits have
invertebrates (Montell 2005; Kahn-Kirby and Barg-
mann 2006). The Caenorhabditis elegans TRPV subunit
OSM-9 is found in the ciliated endings of neurons that
sense touch to the nose (Colbert et al. 1997). Nose
TRPV subunit, OCR-2, which depend on each other for
localization to cilia (Tobinet al. 2002). The Drosophila
TRPV subunits IAV and NAN (similar to OSM-9 and
OCR-2, respectively) similarly depend on each other for
localization to chordotonal cilia (Kim et al. 2003; Gong
1Present address: Department of Molecular and Cellular Biology,
Harvard University, Cambridge, MA 02138.
2Present address: Office of the Director, National Institutes of Health,
Bethesda, MD 20892.
3Corresponding author: Department of Molecular Biophysics and Bio-
chemistry, Yale University School of Medicine, SHM CE30, New Haven,
CT 06520-8024. Email: firstname.lastname@example.org
Genetics 175: 93–105 ( January 2007)
the hypothesis that the coexpressed OSM-9/IAV and
OCR-2/NAN subunits form obligate heteromers for
proper localization to cilia and for function.
Here, we find that three coexpressed C. elegans TRPV
subunits (OCR-1, -2, and -4) apparently form a complex
mixture of functionally redundant homomeric and
heteromeric TRPV channels to control neurotransmit-
ter release from neuroendocrine cells. These channels
can be inactivated by a dominant-negative OCR-2 sub-
unit to reveal a defect in egg-laying behavior not seen
in any of the single subunit knockouts. Further, the
obligate partner of OCR-2 in sensory neurons, OSM-9,
although coexpressed with the other channel subunits
in the neuroendocrine cells, does not function with
them in these cells.
MATERIALS AND METHODS
C. elegans strains: All strains except those containing dpy-
20(e1282ts) were grown at 20? and maintained using standard
methods (Brenner 1974). Worms containing dpy-20(e1282ts)
were grown at 25?. The strains used in this study included N2
wild type, LX671 ocr-2(vs29) IV, LX843 ocr-2(ak47) IV, CX10
osm-9(ky10) IV, LX844 ocr-1(ok132) V, LX979 ocr-1(ak46) V,
LX950 ocr-4(vs137) IV, LX980 ocr-4(vs137) IV; ocr-1(ok132) V,
LX981 ocr-2(ak47) ocr-4(vs137) IV, LX982 ocr-2(ak47) ocr-
4(vs137) IV; ocr-1(ok132) V, LX842 ocr-2(vs29) osm-9(ky10) IV,
LX748 ocr-2(ak47) osm-9(ky10) IV, LX983 ocr-2(ak47) osm-
9(ky10) IV; ocr-1(ak46) V, LX984 ocr-4(vs137) osm-9(ky10) IV,
MT13113 tdc-1(n3419) II, LX845 ocr-2(ak47) IV; ocr-1(ok132) V,
LX669 unc-44(e362) ocr-2(vs29) dpy-20(e1282ts) IV, LX670 ocr-
2(vs29) dpy-20(e1282ts) IV, LX725 ocr-2(ak47) dpy-20(e1282ts)
IV, MT8189 lin-15(n765ts), and LX491 goa-1(n1134) I; lin-
ocr-4 deletion mutant: An ocr-4 deletion (vs137) was gener-
ated using standard C. elegans gene knockout methods (Hess
et al. 2005). vs137 has a 688-bp deletion with 1 base inserted
(uppercase ‘‘T’’ below). The resulting sequence around the
Behavioral assays: Animals for behavioral assays were
isolated as late L4 larvae and aged 11.5 hr at 20? (Figure
1C),24hrat25?(Figure 2D),or 36hr at20?(allother figures)
to obtain precisely staged adults. Numbers of unlaid or
prematurely laid eggs were measured as in Chase and Koelle
(2004) or Jose and Koelle (2005), respectively. Nose touch
avoidance (Kaplan and Horvitz 1993) and osmotic avoid-
ance (Hilliard et al. 2002) assays were adapted as described
below. Worms were placed on agar plates with no bacteria and
assayed 10–40 sec later. For nose touch avoidance, an eyelash
was placed in the path of an advancing worm to cause head-on
collisions and a response (stopping forward movement and
starting a reversal within 3 sec) was scored. vs29 animals failed
vs29 animals attempted to move under it. For osmotic
avoidance, a 100-nl drop of 2 m fructose (Sigma, St. Louis)
was placed in the path of an advancing worm and a response
(stopping forward movement, starting a reversal within 3 sec,
briefly stopped forward movement and then advanced into
the drop, whereas vs29 animals briefly stopped forward
movement, initiated a short reversal, and then advanced into
the drop. For transgenic experiments, animals that showed
expression of the cotransformation marker were chosen from
five independent transgenic lines, and 40 eggs laid by animals
from each line were assayed. Student’s t-test was used to
calculate 95% confidence intervals for numbers of eggs shown
in Figure 1, A–C. In all other assays, 95% confidence intervals
for a single proportion were calculated using Wilson’s esti-
mates, and P-values for comparison of two proportions were
calculated using the proportion of pooled values (Moore and
Transgenes: Germline transformation was as described by
attempted using the cosmids C07G1 and T09A12 (i and ii,
org/supplemental/), and a plasmid (iii in supplemental
Figure S1 at http:/ /www.genetics.org/supplemental/) with
ocr-2 genomic DNAcontaining 2.4 kbupstream of theinitiator
ATG, the coding region, and 1.0 kb of downstream sequences.
A total of 10 ng/ml of each clone and 10 ng/ml of myo-2Tgfp
(co-injection marker, gift of A. Fire, Stanford University) was
injected into vs29 animals. For OCR-2 overexpression experi-
ments, cDNA encoding OCR-2 (gift from C. Bargmann,
Rockefeller University) or encoding OCR-2(Y395F) was used
to replace the ocr-2 coding region in supplemental Figure
10 ng/ml of myo-2Tgfp was injected into wild-type animals. To
express full-length OCR-2TGFP or OCR-2(Y395F)TGFP, the
gfp gene from pPD95.69 (gift of A. Fire) was fused to the wild-
type cDNA construct above or the OCR-2(Y395F) cDNA to
make fusion proteins with green fluorescent protein (GFP)
precisely after the C-terminal residue of OCR-2 or OCR-
2(Y395F), respectively. These were injected at 20 ng/ml with
50 ng/ml of the co-injection marker pL15EK (Moresco and
Koelle 2004) into MT8189 animals. For overexpression of C.
elegans TRPV genes, a genomic region for each was amplified
(GeneAmp XL, Applied Biosystems, Foster City, CA), contain-
ing coding regions along with 59 and 39 regulatory regions
extending to the neighboring genes. These were injected at
50 ng/ml with 10 ng/ml of myo-2Tgfp (co-injection marker)
into vs29 animals.
fusion constructs were made on the basis of the method of
Hobert (2002) as follows: 59 and 39 regulatory regions
(extending to the neighboring genes) were amplified and
fused byoverlapextension PCR tothegfp geneamplified from
pPD95.69. These were injected at 20 ng/ml along with the
coinjection marker pL15EK (50 ng/ml) into MT8189 animals.
We alsomadereporter constructs analogous tothose ofTobin
et al. (2002) lacking the 39 untranslated region (UTR) of ocr-2:
the 59 regulatory region or the 59 regulatory region plus the
coding region through the third exon was fused to gfp coding
sequences in pPD95.69 to make transcriptional (pAJ12) or
translational (pAJ11) reporters, respectively. These GFP con-
structs were coinjected with pL15EK (50 ng/ml) into MT8189
animals. Injection of pAJ11 and pAJ12 at 200 ng/ml labeled
the same cells as the PCR fusion products, but uv1 and a
number of other cells were much more strongly labeled by the
PCR fusion products injected at 20 ng/ml, apparently because
the PCR fusion products contained the ocr-2 39 UTR lacking in
pAJ11 and pAJ12.
The coding sequences of ocr-2 rescuing construct iii
(in supplemental Figure S1 at http:/ /www.genetics.org/
supplemental/) were replaced with coding sequences for the
S1 subunit of pertussis toxin PTx to inactivate Gaoor with the
release. A total of 10 ng/ml of toxin construct and 10 ng/ml
of pAJ12 (co-injection marker) was injected into wild-type
animals. Our TTx cDNA had a polymorphism that changes
94 A. M. Jose et al.
the Ga protein GOA-1 and a set of TRPV channels are
required for function in mechanically deformed endo-
crine cells. This parallels the requirement for the Ga
protein ODR-3 and OCR-2/OSM-9 TRPV channels in
et al. 2002). In these cases, the mechanical stimulus
might be transduced by G-protein-coupled receptors
that act through Ga proteins to regulate TRPV chan-
nel activity (Figure 8). Such an arrangement underlies
mammalian taste (Zhang et al. 2003), Drosophila vi-
sion (Montell et al. 1985), and C. elegans olfaction
(Colbert et al. 1997).
We thank the Caenorhabditis Genetics Center for strains, the Yale
Center for Cell and Molecular Imaging for microscopes, H. Qin for
microscopy advice, C. Bargmannfor cDNA clones, J. Tanis for the PTx
clone, P. De Camilli for the TTx clone, and S. Jordt for critical reading
of the manuscript. This work was supported by National Institutes of
Health grant NS03918.
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Communicating editor: D. I. Greenstein
Mixed Heteromeric TRPV Channels105