Use it or lose it: Mechanically activated cation channel essential to heart health

Research Areas:

Cardiac myocytes, cardiac hypertrophy, calcium channels, mechanoreception, Fura-2, Mice

Imaging Needs:

Fast frame rates

Imaging System (stretch-induced Ca2+ signaling in neonate cardiomyocytes):
  • Inverted IX71 microscope (Olympus)
  • UApo 20 x/0.75 objective lens (Olympus)
  • Fura-2 acetoxymethyl ester fluorescent calcium indicator
  • Excitation: 340 and 380 nm
  • Lambda DG-4 Ultra High Speed Wavelength Switcher (Sutter Instruments)
  • Hamamatsu ORCA-Flash 2.8 sCMOS camera
  • MetaFluor software (Molecular Devices)
Imaging System (cell shortening and Ca2+ signaling in adult cardiomyocytes):
  • Inverted IX71 microscope (Olympus)
  • UApo N340 x20 water immersion objective lens (Olympus)
  • Excitation / recording: 340 nm / 405 and 480 nm
  • Evolve EM-CCD camera (Photometrics)
  • MetaMorph software (Molecular Devices)
Imaging System (immunocytochemistry):
  • Alexa Flour 488-conjugated IgG (Life Technologies)
  • Fluoview FV1000 confocal microscope (Olympus) mounted on an IX81 epifluorescence microscope (Olympus)
  • UPlanSApo x60/1.35 oil immersion objective lens (Olympus)
Imaging the living brain

See how Misha Ahrens, Philipp Keller, and colleagues use lightsheet microscopy to visualize the actions of individual neurons in the whole brain, live and in real time. Read now.


How does the heart respond to mechanical stress?

The physical load and mechanical stresses of pumping blood are crucial to healthy heart development and function. Cardiac muscle responds to exercise and other load increases with healthy growth, while prolonged hypertension can lead to pathological hypertrophy. Reductions in load, as with bed rest, lead to atrophy. However it’s not clear how cardiomyocytes transduce mechanical forces into the molecular responses that maintain heart muscle.

Cardiac myocytes are joined at their ends both electrically and mechanically, at specialized intercellular junctions called intercalcated discs. These discs remodel in response to haemodynamic stress, becoming physically stronger following increased work and less ordered after load reduction. Genetic and laboratory evidence suggests involvement of these intercalcated discs in heart disease. Understanding of the mechanism by which mechanical forces maintain their health could provide a promising therapeutic target, and improve understanding of cardiac development, trophic remodeling, and pathophysiology.


Muraki et al. have shown that cation channels of the transient receptor potential (TRP) family, specifically TRP vanilloid type 2 (TRPV2), are activated by mechanical stimulation.1 Highly localized to intercalcated discs in mammals, TRPV2 is upregulated in cardiac dystrophy. The researchers set out to show whether this receptor might be a primary player in cardiac mechanoreception.


TRPV2 is critical for the maintenance of cardiac structure and function in mice
Katanosaka Y, Iwasaki K, Ujihara Y, Takatsu S, Nishitsuji K, Kanagawa M, Sudo A, Toda T, Katanosaka K, Mohri S, Naruse K
Nat Commun. 2014 May 29; 5:3932. PMCID: PMC4050274.

To clarify the receptor’s role in cardiac muscle, Katanosaka et al.2 examined cardiac and cardiomyocyte morphology and function in TRPV2-deficient mice. Within days of tamoxifen-triggered TRPV2 deficiency, adult males showed severe impairment in the heart’s pumping function, together with widened QRS complexes and defects in interventricular conduction, leading to mortality after about 10 days.

Immunocytochemistry and electron microscopy revealed distortions of the intercalculated disc structure with TRPV2 deficiency. However, individual myocytes showed no initial dysfunction in morphology or shortening. Calcium channel transients following electrical stimulation—captured using the fluorescent calcium indicator Fura-2 and a Photometrics Evolve EM-CCD camera—remained normal at day four, as did the localization of intracellular calcium channels. However, both degraded by day nine, accompanied by disorganization of the contractile cytoskeleton.

In cultured newborn cardiomyocytes, TRPV2 deficiency prevented normal development of the intercalated disc. Calcium transients in response to stretch stimulation—viewed using a Hamamatsu ORCA-Flash2.8 sCMOS camera—were completely elimintated in TRPV2-deficient neonatal cardiomyocytes, as was the normal stretch-induced release of insulin-like growth factor 1 (IGF-1). Consistent with this observation, administration of exogenous IGF-1 partially prevented loss of cardiac pump function in TRPV2-deficient hearts.

Katanosaka et al. conclude that TRPV2 plays an essential role in maintaining mechanical integrity at intercalcated discs as well as calcium signaling in response to the mechanical force exerted by cardiomyocyte contraction. The authors propose a model by which stretching forces activate TRPV2—either directly or indirectly—which in turn maintains normal secretion of IGF-1 and healthy cardiac morphology and function. They propose further study to clarify the molecular mechanism of mechanotransduction mediated by TRPV2 in cardiomyocytes.


Katanosaka et al. traced intracellular calcium waves with the help of Hamamatsu’s ORCA-Flash2.8 camera. Recently developed lightsheet microscopy technology using Hamamatsu’s ORCA-Flash4.0 camera enables Misha Ahrens and colleagues to monitor functional measures in the whole brain—read Seeing the Living Brain.


  1. Muraki, K. et al. TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes. Cir. Res. 93, 829–838 (2003).
  2. Katanosaka, et al. TRPV2 is critical for the maintenance of cardiac structure and function in mice. Nat Commun. 2014 May 29; 5:3932. PMCID: PMC4050274.
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