Signaling by Sensory Receptors

Signaling by Sensory Receptors David Julius1 and Jeremy Nathans2 1Department of Physiology, University of California School of Medicine, San Francisco, California 94158 2Department of Molecular Biology and Genetics, Johns Hopkins Medical School, Baltimore, Maryland 21205 Correspondence: [email protected] and [email protected] SUMMARY Sensory systems detect small molecules, mechanical perturbations, or radiation via the activation of receptor proteins and downstream signaling cascades in specialized sensory cells. In vertebrates, the two principal categories of sensory receptors are ion channels, which mediate mechanosensation, thermosensation, and acid and salt taste; and G-protein-coupled receptors (GPCRs), which mediate vision, olfaction, and sweet, bitter, and umami tastes. GPCR- based signaling in rods and cones illustrates the fundamental principles of rapid activation and inactivation, signal amplification, and gain control. Channel-based sensory systems illus- trate the integration of diverse modulatory signals at the receptor, as seen in the thermosensory/pain system, and the rapid response kinetics that are possible with direct mechanical gating of a channel. Comparisons of sensory receptor gene sequences reveal numerous exam- ples in which gene duplication and sequence divergence have created novel sensory specific- ities. This is the evolutionary basis for the observed diversity in temperature- and ligand- dependent gating among thermosensory channels, spectral tuning among visual pigments, and odorant binding among olfactory receptors. The coding of complex external stimuli by a limited number of sensory receptor types has led to the evolution of modality-specific and species-specific patterns of retention or loss of sensory information, a filtering operation that selectively emphasizes features in the stimulus that enhance survival in a particular ecological niche. The many specialized anatomic structures, such as the eye and ear, that house primary sensory neurons further enhance the detection of relevant stimuli. Outline 1 Introduction 5 Evolution and Variation 2 Receptors: Detection and Transduction 6 Concluding Remarks 3 Structural Basis of Sensory References Receptor Activation 4 The Logic of Sensory Coding Editors: Lewis Cantley, Tony Hunter, Richard Sever, and Jeremy W. Thorner Additional Perspectives on Signal Transduction available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a005991 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a005991 1 D. Julius and J. Nathans 1 INTRODUCTION notable example is the retina, where visual pigments, to- gether with other components of the phototransduction An organism’s perception of the world is filtered through its pathway, are localized within outer segments of rod and sensory systems. The properties of these systems dictate the cone photoreceptor cells at near millimolar concentra- types of stimuli that can be detected and constrain the ways tions, thereby enhancing light sensitivity and transduction in which these stimuli are reconstructed, integrated, and in- efficiency (Yau and Hardie 2009). Another example is seen terpreted. Here we discuss how sensory signals are received in the cochlea, where sound pressure waves are transmit- and transduced, focusing on the first steps in the complex ted through the middle ear to induce a localized and fre- process of perceiving an external stimulus. A recurrent quency-dependent distortion of the basilar membrane in theme is the way in which the biochemical and biophysical the cochlea. Progressive changes in both the mechanical properties of sensory receptor molecules, and the neurons properties of the basilar membrane and the electrical prop- in which they reside, have been sculpted by evolution to erties of the auditory hair cells along the length of the coch- capture those signals that are most salient for the survival lea generate a tonotopic map in which the amplitudes of and reproduction of the organism. As a result, some classes different frequency components in a complex sound are re- of sensory receptors, such as the night vision receptor rho- flected in the magnitudes of auditory receptor activation at dopsin, show great conservation, whereas others, such as different locations within the cochlea (Roberts et al. 1988). olfactory receptors, show great diversity. Evolutionary comparisons are fascinating at many 2 RECEPTORS: DETECTION AND TRANSDUCTION levels, not least of which is their power to highlight the logic of the stimulus–response relationship. For example, Both GPCRs and ion channels contribute to sensory trans- honeybees can see UV light, enabling them to locate sour- duction pathways by initiating or modulating stimulus- ces of nectar and pollen based on the UV reflectance of evoked responses (Fig. 1; Table 1). In vertebrates, GPCRs flower petals (Kevan et al. 2001), whereas humans and predominate as stimulus detectors in vertebrate visual Old World primates have excellent sensitivity and chro- and olfactory receptor cells. In contrast, recent studies sug- matic discrimination at longer wavelengths, permitting gest that fly olfactory neurons use ionotropic glutamate re- the identification of red, orange, and yellow fruit against ceptor-like channels to detect some classes of odorants a background of green foliage (Mollon 1989). Star-nosed (Benton et al. 2009), revealing a striking divergence of sig- moles use a specialized mechanoreceptive organ on their nal transduction mechanisms between insect and verte- snout to locate meals and navigate through lightless sub- brate chemosensory systems. Ion channels predominate terranean tunnels (Catania 2005), and pit vipers have in the detection of auditory and somatosensory stimuli, evolved thermoreceptive organs to detect the infrared and both GPCRs and ion channels serve as stimulus detec- radiation emitted by their warm-blooded prey (Campbell tors in the gustatory (taste) system. et al. 2002). In each of these cases, evolution has fine-tuned Because GPCRs transduce information through multi- a sensory organ through anatomical and/or molecular component second-messenger-based “metabotropic” sig- changes to enhance the detection of relevant stimuli. naling pathways (Henrik-Heldin et al. 2012), they endow For simplicity, we focus on eukaryotic sensory systems, physiological systems with a tremendous capacity for signal in which G-protein-coupled receptors (GPCRs) and ion amplification (Fig. 2). In vertebrate chemosensory and channels predominate as sensory receptors. The one excep- visual systems, GPCR-based signaling enables sensory cells tion is mechanosensation, in which the molecular basis to detect nanomolar concentrations of ligands or single of membrane stretch detection has been beautifully de- photons, respectively. Such high sensitivity is possible lineated in bacteria but remains less clear in eukaryotes. because a single GPCR, during its active lifetime, can acti- Thus, our discussion of mechanosensation is focused vate dozens to hundreds of G proteins, and each activated largely on prokaryotic systems. Wealso describe the diverse G protein in conjunction with its associated target enzyme cast of downstream transduction pathways and the manner can synthesize or destroy thousands of second-messenger in which receptors and transduction pathways are regulated molecules. This type of signaling cascade has been most to terminate signaling and set receptor sensitivity. thoroughly analyzed in vertebrate rod photoreceptors, Before discussing individual receptors, it is worth not- where light-evoked activation of a single rhodopsin mol- ing that the physiological attributes of sensory systems are ecule leads to the activation of about 500 downstream dictated not only by the molecular properties of receptor effector proteins [the G protein transducin and its associ- molecules and their associated signal transduction pro- ated cyclic (c)GMP phosphodiesterase], with the conse- teins, but also by the architecture of the sensory organs, quent hydrolysis of about 100,000 molecules of cGMP cells, and subcellular structures in which they reside. A per second (Fig. 1A) (Stryer 1986; Arshavsky et al. 2002). 2 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a005991 Sensory Receptors The reduction in cytosolic cGMP leads to the closure of timescale of tens of milliseconds (Arshavsky et al. 2002). cGMP-gated ion channels in the outer segment plasma Once phosphorylated, the receptor is capped by the inhi- membrane, thereby hyperpolarizing the cell and decreasing bitory protein arrestin, which blocks subsequent G-protein the release of the neurotransmitter glutamate onto bipolar activation. In hormone and neurotransmitter receptor sys- cells, the second-order neurons within the retina. tems, arrestin binding also facilitates receptor endocyto- A similar biochemical logic governs signaling in verte- sis and recycling. In contrast, in the photoreceptor outer brate olfactory sensory neurons, where activation of G-pro- segment, rhodopsin remains stably localized to the disc tein-coupled odorant receptors increases the synthesis of membrane. Rhodopsin is recycled to its dark state by the cAMP, which binds directly to and thereby opens cyclic- combination of dephosphorylation and exchange of the nucleotide-gated ion channels in the plasma membrane photoisomerized all-trans retinal chromophore for a new of olfactory cilia (Fig. 1B). The resulting depolarization moleculeof11-cisretinal,reactionsthatoccuronatimescale

Load more