Did you know...

The Fly.jpg
Figure 1. A. Drosophila eye photoreceptor cells contain TRP channels, while the human TRPC homologs are involved in lung permeability B (figure adapted from[4,5]).

…that the protein conducting a fly’s visual phototransduction has the same origin as those regulating human lung permeability? 

From Drosophila to humans, the transient receptor potential (TRP) family of proteins is evolutionarily conserved [12] (Figure 1).  Two TRP proteins of the canonical subfamily, TRPC1 and TRPC4, are molecular candidates of store-operated Ca2+ (SOC) entry channel subunits involved in increasing human lung permeability. 

In 1969, Cosens and Manning discovered the Drosophila trp gene by identifying an eye mutation in flies with visual deficiencies [3]. While the normal photoreceptor cells had a sustained membrane depolarization, the mutant cells only had a transient depolarization in response to continuous light. This phenomenon of transient membrane depolarization led to the origin of the name “trp” (transient receptor potential). Twenty years later, Montell proposed that “trp is the structural gene for the light-sensitive channels” [6]. Around the same time, Putney hypothesized capacitative Ca2+ entry [7] to describe agonist-induced endoplasmic reticulum Ca2+ release followed by Ca2+ influx through plasma membrane channels. Now, this mechanism is widely referred to as SOC entry [8]. In 1993, Minke linked TRP channel and SOC entry together and hypothesized that the Drosophila TRP channel may actually be the molecular basis of the mammalian SOC channels [910].

The molecular basis of the SOC channels is complex and involves different proteins including TRP channel proteins in different animal and tissue types.  In 1995, a human homolog of the Drosophila TRP channel, TRPC1 was identified [1].  While the physiological role of TRPC proteins is still unclear, a pathophysiological effect has been identified.  Knockdown of TRPC1 reduced thapsigargin-induced SOC entry and calcium current in human pulmonary artery endothelial cells [11].  Overexpression of TRPC1 increased thrombin-induced SOC entry and lung permeability in both human pulmonary artery and microvascular endothelium [12].  In addition to TRPC1, TRPC4 was found to have a similar role. At the beginning of the 21st century, TRPC4 knockout mice were generated [1314]. This type of mouse has lower lung microvascular permeability after thrombin exposure when compared to wild type animals, indicating that TRPC4 also contributes to the increase in lung permeability [14]. From Drosophila visual phototransduction to human lung permeability, the trp family of genes is conserved during evolution [1214].   



  1. Wes PD, Chevesich J, Jeromin A, Rosenberg C, Stetten G, Montell C. Trpc1, a human homolog of a drosophila store-operated channel. Proceedings of the National Academy of Sciences of the United States of America. 1995;92:9652-9656

  2. Jegla TJ, Zmasek CM, Batalov S, Nayak SK. Evolution of the human ion channel set. Combinatorial chemistry & high throughput screening. 2009;12:2-23

  3. Cosens DJ, Manning A. Abnormal electroretinogram from a drosophila mutant. Nature. 1969;224:285-287

  4. http://www.sciencedaily.com/releases/2012/10/121011141441.htm.

  5. http://www.biovisuals.com/illust/pulm.edema_300x257.gif.

  6. Montell C, Rubin GM. Molecular characterization of the drosophila trp locus: A putative integral membrane protein required for phototransduction. Neuron. 1989;2:1313-1323

  7. Putney JW, Jr. A model for receptor-regulated calcium entry. Cell calcium. 1986;7:1-12

  8. Venkatachalam K, van Rossum DB, Patterson RL, Ma HT, Gill DL. The cellular and molecular basis of store-operated calcium entry. Nature cell biology. 2002;4:E263-272

  9. Hardie RC, Minke B. Novel Ca2+ channels underlying transduction in drosophila photoreceptors: Implications for phosphoinositide-mediated Ca2+ mobilization. Trends in neurosciences. 1993;16:371-376

  10. Selinger Z, Doza YN, Minke B. Mechanisms and genetics of photoreceptors desensitization in drosophila flies. Biochimica et biophysica acta. 1993;1179:283-299

  11. Brough GH, Wu S, Cioffi D, Moore TM, Li M, Dean N, Stevens T. Contribution of endogenously expressed trp1 to a Ca2+-selective, store-operated Ca2+ entry pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2001;15:1727-1738

  12. Paria BC, Vogel SM, Ahmmed GU, Alamgir S, Shroff J, Malik AB, Tiruppathi C. Tumor necrosis factor-alpha-induced trpc1 expression amplifies store-operated Ca2+ influx and endothelial permeability. American journal of physiology. Lung cellular and molecular physiology. 2004;287:L1303-1313

  13. Freichel M, Suh SH, Pfeifer A, Schweig U, Trost C, Weissgerber P, Biel M, Philipp S, Freise D, Droogmans G, Hofmann F, Flockerzi V, Nilius B. Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in trp4-/- mice. Nature cell biology. 2001;3:121-127

  14. Tiruppathi C, Freichel M, Vogel SM, Paria BC, Mehta D, Flockerzi V, Malik AB. Impairment of store-operated Ca2+ entry in trpc4(-/-) mice interferes with increase in lung microvascular permeability. Circulation research. 2002;91:70-76

Author: Ningyong Xu, January 2014
Chief editor: Donna Cioffi, Ph.D.
Co-editor: Salina Gairhe, Ph.D.

Email Newsletters

Connect With Us