The touch of a fly

Our sense of touch has an innate connection with our emotions. Gentle touches are soothing for not only us but also other animals. For example, classic experiments by psychologist Harry Harlow in the 1950s found that an infant monkey raised with two robots, one providing food and the other wearing soft cloth, spends more time cuddling with the cloth robot1. When scared, the infant monkey also goes to the cloth robot for protection. Clearly, there is a special pathway that guides touch sensation to the depths of animal instincts. Working out this pathway requires knowledge about the neural circuitry processing touch sensation.

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Toward a Molecular Lego Kit for Engineering Specialized Channels

“What I cannot create, I do not understand.” — Richard Feynman (1988)

An organism’s ability to sense the world ultimately relies on specialized proteins in its sensory neurons to probe the external world on behalf of the entire organism. Channels, a group of proteins that act as gatekeepers of ions, are often delegated to the front end of the job. As a result, highly specialized channels, such as those that sense odors, temperature, and even touch, have evolved in all corners of the world. Over the years, the genetic identities of many such channels have been demystified. Our current challenge lies in pinpointing the nanoscopic means by which they sense the world. To achieving this goal, an inevitable path is to locate the intramolecular modules (often referred to as domains) that grant channels their special ability to sense the environment. Several remarkable studies in recent years have made significant progress in attacking this problem.

KcsA

Only a few years ago, in 2011, the Sternson group exploited the properties of specialized domains to engineer new ligand-gated channels, which they called PSAMs2. First, the Sternson group made the critical observation that ligand-gated (i.e. molecule-sensing) ion channels can be divided into two somewhat independent domains, the ligand-binding domain and the ion channel domain. By screening candidate mutations in the ligand-binding domain of a starter channel, they were able to engineer the channel to lose its innate affinity to its natural ligand and acquire a preference for a synthetic molecule. By transplanting this new ligand binding domain onto other excitatory and inhibitory ion channel domains, the Sternson group successfully created novel excitatory and inhibitory channels. These channels now specialize in binding synthetic ligands that have never occurred in any biological system and are used as a tool to manipulate neuron activities.

Recent work by researchers in the Jan labs identified another elegant example of specialized domains in a touch-sensitive channel, NompC3. NompC has a long tail of short, repeated sequences known as Ankyrin repeats. These Ankyrin repeats connect the NompC channel, which resides on the surface of the cell, to the cell’s cytoskeleton, much as a ship’s anchor secures its vessel to the bottom of the ocean. When the cell surface is deformed by touch, it changes the distance between NompCs and the cytoskeleton, causing these Ankyrin chains to pull on the channels, just as a ship’s anchor will pull on the ship when ocean waves begin pushing the ship away. In the case of NompC, however, the Ankyrin chain can actually pull open the channel and, quite unexpectedly, plays an important role in defining the distance between the cell surface and cytoskeleton (i.e. the depth of the ocean in the ship analogy). Finally, transplanting the Ankyrin chain to a touch-insensitive channel renders the new channel touch-sensitive, just like the original NompC channel. The Ankyrin chain can therefore serve as a Lego piece for making touch-sensing channels.

Although specialized domains are common, they are not a requirement for specialized channels. For example, the search for a heat-sensitive domain in the thermosensitive TrpV1 channel has yielded largely non-overlapping regions of the protein. Facing this paradox, the Chanda group4 built on theoretical work that proposed that the temperature-gating properties of a channel might result from its general interaction with the cell membrane5. By changing the membrane-interaction properties of a small number of amino acids in a potassium channel, which is normally temperature insensitive, the researchers were able to create new channels that were just as temperature-sensitive as the natural ones. These manipulations also removed the potassium channel’s intrinsic voltage sensitivity, implying a shared mechanism between these two intuitively different senses.

Perhaps to Mr. Feynman’s disappointment, creating channels on a blackboard using only a handful of principles is still a dream of the future. In all three of these examples, rationality dictates the general directions of the research paths, but the details are left to hard work and serendipity. Nonetheless, the ability to grant new sensing properties to old channels by means of rational design should confer a great sense of achievement, as deserved by those who steal secrets from nature.

References:

  1. Doyle, D. A. et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69–77 (1998).
  1. Magnus, C. J. et al. Chemical and genetic engineering of selective ion channel-ligand interactions. Science 333, 1292–6 (2011).
  1. Zhang, W. et al. Ankyrin Repeats Convey Force to Gate the NOMPC Mechanotransduction Channel. Cell 162, 1391–1403 (2015).
  1. Chowdhury, S., Jarecki, B. W. & Chanda, B. A molecular framework for temperature-dependent gating of ion channels. Cell 158, 1148–58 (2014).
  1. Clapham, D. E. & Miller, C. A thermodynamic framework for understanding temperature sensing by transient receptor potential (TRP) channels. Proc. Natl. Acad. Sci. U. S. A. 108, 19492–7 (2011).

 

 

Getting a Sense of the Sixth Sense

“This “proprioception” is like the eyes of the body, the way the body sees itself.”

– Oliver Sacks in The Man Who Mistook His Wife For A Hat

Think about baseball. Right before the pitcher throws the ball, the ball and his hand are behind him, out of his sight. Yet, he knows where his hand and the ball are and how both are moving. How is this possible? The pitcher can tell where the ball is using his sixth sense. No, this is not the same sixth sense that the character played by Haley Joel Osment has in the movie The Sixth Sense. This sixth sense is known as proprioception (pronunciation: PRO-pree-o-SEP-shən). Proprioception is the sense that allows us to determine the relative position and movement of our body parts in space. So what do we know about proprioception? How does it work?

Image of Charles Sherrington who coined the term

The word, “proprioception” was coined by the British scientist Charles Sherrington in 1906. Sherrington identified two types of sensory neurons that innervate the muscle that are now known to underlie proprioception. These neurons are known as muscle spindles and Golgi tendon organs. Muscle spindles innervate muscle fibers and detect changes in muscle length while Golgi tendon organs innervate the junction between muscles and detect changes in muscle tone (the effort exerted by muscle). Unlike the other five senses, proprioception does not have a designated sensory organ; rather information is collected from the whole body. This information is sent up through the spinal cord to the cerebellum where the positions of body parts in space are calculated.

While the neurons involved in proprioception have long been identified, the molecular mechanisms underlying this sense are just beginning to be understood. In a recent paper, Woo et. al (2015) identify the mechanoreceptor Piezo2 as a mechanically-gated ion channel involved in translating muscle movement to electrical signals that are then transmitted to the central nervous system. When a muscle moves, the membrane of the neurons innervating it also moves, creating a mechanical force that opens these ion channels, allowing positively charged ions to flow into the neuron and thus creating an electrical impulse.

The muscle spindle and Golgi tendon organ are the proprioreceptors that detect and transmit changes in muscle length and tone to the rest of the nervous system (image source: http://www.medicalook.com/human_anatomy/organs/Proprioceptors.html)

The first evidence for Piezo2’s involvement in proprioception was its strong expression on muscle spindles and Golgi tendon organs in mice. The authors also demonstrate that the electrophysiological response properties of these neurons in response to mechanical stimulation resemble that of cells expressing the Piezo2 channel alone. Finally, the authors show that mice lacking Piezo2 in the proprioceptive neurons (conditional knockout mice) have severely impaired limb coordination, suggesting that Piezo2 is necessary for proprioception. [1] These findings have opened the door for scientists to further understand the molecular mechanisms that give rise to proprioception within the muscle spindles and Golgi tendon organs. However, it has to be noted that there is a lot more to proprioception beyond these two neuronal groups.

Longo and Haggard (2010) argue that while the cerebellum receives information on muscle stretch and tone from proprioceptive neurons, this information on its own is insufficient for the person to know where his body is in space. Information such as body size and shape are also crucial for this process. Longo and Haggard hypothesize that there must be a “stored body model” that the brain learns over time and is used as a reference map for information such as the length of your arm. [2] It is also suggested that the development of this map includes information not just from the proprioceptive neurons but also from other senses, primarily vision. [3] This could explain why a child learning the piano for the first time needs to look at his fingers to make sure he hits the right notes. However, a master pianist can play blindfolded and still know exactly where each finger is relative to the other.

Proprioception, the sixth sense, is a critical one. It enables many of the daily actions that we do without thinking. A loss of this proprioceptive sense is almost unimaginable to many of us, but it does happen. Damage to the nerves from injury or infection can lead to loss of this sense; affected people are unable to tell where their body parts are when they cannot see them (Ian Waterman is one such person). Therefore, developing a better understanding of how proprioception works and what the mechanisms involved are is vital. So, how are visual and proprioceptive inputs assimilated to create this “stored body model”? How do the molecular mechanisms underlying proprioception change as we develop this mental map of our body or as we learn to play the piano? Is Piezo2 expression or function involved in this? It will be interesting to see these questions answered as we get a better sense of proprioception.

Reference:

  1. Woo, S-H., Lukacs, V., de Nooij, J.C., Zaytseva, D., Criddle, C.R., Francisco, A., Jessel, T.M., Wilkinson, K.A., Patapoutian, A. (2015) Piezo2 is the principal mechanotransduction channel for proprioception Nature Neuroscience
  2. Longo, M.R., Haggard, P. (2010) An implicit body representation underlying human position sense PNAS Vol. 107, No. 26
  3. Blanke, O., Slater, M., Serino, A. (2015) Behavioral, neural and computational principles of bodily self-consciousness Neuron Vol. 88
  4. http://www.hhmi.org/biointeractive/ian-waterman-compensating-proprioceptive-loss