Proceedings of The Physiological Society
Durham University (2010) Proc Physiol Soc 21, PC39
Whirlin function in proprioceptive mechanotransduction
J. C. de Nooij1, A. Simon3, S. Doobar1,2, K. P. Steel4, R. W. Banks5, G. S. Bewick3, T. M. Jessell1,2
1. Dept. of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, United States. 2. Howard Hughes Medical Institute, New York, New York, United States. 3. School of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom. 4. Welcome Trust Sanger Institute, Welcome Trust Genome Campus, Cambridge, United Kingdom. 5. School of Biological & Biomedical Sciences, University of Durham, Durham, United Kingdom.
Proprioceptive sensory feedback is critical for many aspects of motor control. This form of sensory feedback derives largely from specialized mechanoreceptors located within muscles: the muscle spindle (MS; responsive to changes in muscle length) and the Golgi tendon organ (GTO; responsive to changes in muscle tension) (1). Anatomical and physiological analysis has provided insight into the sensory transduction process in MS and GTO afferents and has demonstrated that the afferent stretch response is primarily carried by sodium currents (2). The stretch-evoked MS-afferent impulse frequency is significantly diminished by amiloride, implicating the Degenerin/ENaC family of sodium channels as components of the MS-afferent mechanotransduction channel (3). Glutamate, released from sensory terminals, tonically maintains afferent excitability, possibly by regulating membrane insertion of mechano-transduction channels (4). Despite these recent advances, the molecular mechanisms that underlie the transformation of proprioceptive mechanical stimuli into electrical impulses remain largely unknown. In a molecular screen for new proprioceptor specific molecules, we recently found that whirlin is selectively expressed in proprioceptive sensory neurons in dorsal root ganglia. Whirlin encodes a scaffold protein with important roles in hair cell and photoreceptor sensory transduction (5), raising the possibility that whirlin also functions in the proprioceptive mechanotransduction process. Using an in vitro muscle/nerve preparation, we find that the activation of spindle afferents by mechanical stretch is compromised in whirlin mutant mice when compared to heterozygous mice. Application of exogenous glutamate normalizes afferent stretch-sensitivity. These observations suggest that essential components of the proprioceptive transduction machinery are inefficiently ‘deployed’ in whirler mutant mice. Given that whirlin contains three PDZ-domains, and is known to recruit macromolecular complexes to specific subcellular locations, we speculate that whirlin may function to recruit and/or ensure the proper subcellular localization of a mechano-transduction complex in proprioceptive sensory terminals. Our current studies are aimed at testing this hypothesis. The identification of whirlin provides opportunities to identify additional components of the proprioceptive transduction machinery. The parallel expression of whirlin in proprioceptive muscle afferents, hair cells and photoreceptor cells raises the possibility of a central role for whirlin in diverse sensory transduction processes.
Where applicable, experiments conform with Society ethical requirements