Olfactory Transduction: GPCRs and CNG Channels

Odorant Binding and CNG Channel Activation

• Odorant molecules dissolve in nasal mucus and bind to olfactory receptor proteins on olfactory receptor neuron (ORN) cilia
• Binding initiates a signal transduction cascade for smell perception

GPCR Activation

• Olfactory receptors belong to the G-protein-coupled receptor (GPCR) family
• Odorant binding changes receptor shape, activating the associated G-protein called Golf

Adenylate Cyclase Activation and cAMP Production

• Activated Golf protein stimulates adenylate cyclase (ACIII)
• ACIII converts ATP to cyclic adenosine monophosphate (cAMP)

CNG Channel Opening

• Increased cAMP levels activate cyclic nucleotide-gated (CNG) ion channels
• These channels open, allowing influx of Na⁺ and Ca²⁺ into the neuron

Membrane Depolarization

• Influx of Na⁺ and Ca²⁺ leads to neuron membrane depolarization
• Ca²⁺ activates Cl⁻ channels, causing Cl⁻ efflux and further depolarization

Action Potential Generation and Signal Transmission

• An action potential is generated if depolarization reaches the threshold
• The signal is transmitted to the olfactory bulb via the olfactory nerve (cranial nerve I)

Perception of Smell and Higher Brain Regions

• The olfactory bulb processes signals and relays them to the olfactory cortex and limbic system
• This leads to odor perception and potential emotional or memory associations

Role of Calcium Ions

• Calcium ions (Ca²⁺) regulate olfactory receptor neurons (ORNs)
• Ca²⁺ coordinates recovery to restore baseline activity after odorant stimulation
• Ca²⁺ coordinates adaptation to reduce sensitivity to prolonged or repeated odor exposure

Calcium Influx and Regulation

• CNG channels open when odorants bind to olfactory receptors
• This allows influx of Na⁺ and Ca²⁺, leading to neuronal depolarization and signal transmission
• Ca²⁺ is a key regulator that prevents overstimulation and allows recovery

Calcium-Mediated Signal Termination

• The system must return to its resting state to detect new stimuli after odorant detection
• Ca²⁺ contributes to recovery by activating Ca²⁺/calmodulin-dependent phosphodiesterase (PDE1C)
• PDE1C breaks down cAMP

Restoration of Membrane Potential and Calcium Extrusion

• CNG channels close as cAMP levels decrease, stopping ion influx and restoring membrane potential
• Ca²⁺ is extruded via the Na⁺/Ca²⁺ exchanger (NCX) and Ca²⁺ ATPase pumps ensuring complete recovery

Calcium-Dependent Adaptation

• Olfactory neurons reduce their sensitivity to prevent excessive responses when an odorant persists

Calmodulin Binding

• Ca²⁺ binds to calmodulin (CaM), inhibiting the CNG channels
• Reduces their ability to open even with cAMP present

Phosphodiesterase Activation and Protein Kinases

• Ca²⁺ enhances phosphodiesterase (PDEs) activity, further lowering cAMP levels and preventing prolonged activation
• Ca²⁺ activates protein kinases to phosphorylate and desensitize olfactory receptors
• This reduces their responsiveness to odorants

Odorant Receptor Polymorphisms

• Differences in odor perception is influenced by genetic variations, known as polymorphisms, in odorant receptor (OR) genes including sensitivity, intensity, and subjective pleasantness
• Polymorphisms affect odor sensitivity, intensity, and subjective pleasantness

Diversity of Odorant Receptors

• Humans possess ~400 functional odorant receptor genes, each encoding a receptor for specific odor molecules
• These receptors belong to the G-protein-coupled receptor (GPCR) family, expressed in olfactory receptor neurons
• Polymorphisms alter structure, function, or expression causing variation in odor detection and perception

Single Nucleotide Polymorphisms (SNPs)

• A single base change in a gene can modify how strongly an odor is detected
• The SNP in OR7D4 affects perception of androstenone (sweat, pork) where it can be found unpleasant or neutral/sweet

Copy Number Variations (CNVs)

• Individuals can have more or fewer copies of certain odorant receptor genes
• Variation in OR5A1 influences sensitivity to β-ionone (violets, wine) where people with multiple copies find it more intense and floral

Loss-of-Function Mutations

• Individuals can be unable to detect certain odors from polymorphisms resulting in non-functional odorant receptors
• A mutation in OR2J3 leads to anosmia (inability to smell) for cis-3-hexen-1-ol (fresh cut grass scent)

"One Neuron-One Receptor" Rule

• Each olfactory receptor neuron (ORN) expresses only one type of odorant receptor (OR)
• This precise odor discrimination and encoding is crucial

Odorant Receptor Gene Expression

• The human genome contains ~400 functional OR genes, while mice have over 1,000
• Each ORN selects and expresses one OR gene from the large gene family
• Only one OR gene is expressed, all other OR genes in that neuron are silenced, ensuring monoallelic expression

Choice Mechanism

• The process in which an ORN selects a single receptor is stochastic (random) but follows genetic and epigenetic regulation
• Feedback mechanisms prevent the expression of additional OR genes in the same neuron once an OR gene is activated

Specific Odor Detection and Signal Encoding

• Each ORN is tuned to detect a specific set of odor molecules, expressing only one OR type
• Odor molecules activate different ORNs creating a combinatorial code based on their chemical structure for each smell

Organization in the Olfactory Bulb

• ORNs expressing the same receptor converge onto specific glomeruli in the olfactory bulb
• The brain interprets odor signals efficiently as a result of this spatial arrangement

ORN Distribution

• Neurons expressing the same OR are scattered across broad zones within the olfactory epithelium and are not clustered together, despite each olfactory receptor neuron (ORN) expressing a single type of odorant receptor

Olfactory Epithelium Distribution

• The olfactory epithelium has broad zones without strict compartmentalization for neurons expressing the same receptor

ORN Distribution

• ORNs expressing a specific odorant receptor are randomly distributed within a given zone
• Coverage is ensured and odor detection probability is maximized as a result

Redundancy and Robustness

• Preventing localized damage (infection, injury) from eliminating the ability to detect a specific odor is enabled by spreading ORNs across the epithelium

Enhanced Odor Detection

• Odorant molecules will interact with appropriate ORNs, improving sensitivity to smells from the broad distribution

Effective Signal Integration

• Axons converge onto specific glomeruli in the olfactory bulb, preserving the specificity of odor coding even though ORNs are scattered

Signal Processing

• ORNs that express the same OR send their axons to the same glomerulus in the olfactory bulb despite their broad distribution in the nose
• Scattered neurons signals are processed as a single, unified odor signal from this convergence

Axonal Projections

• Axons converge onto a single glomerulus within the olfactory bulb and although ORNs expressing the same OR are broadly distributed in the olfactory epithelium
• Multiple glomeruli are contained in each olfactory bulb as processing units for distinct odor signals
• There are typically two glomeruli per OR type, one in each olfactory bulb (left and right)

Axonal Targeting

• Molecular guidance cues (cell-adhesion molecules, signaling proteins) usage helps ORNs find the correct glomerulus
• Different ORs influence axonal expression of proteins involved in targeting as the odorant receptor helps in guiding axons

Lateral Inhibition

• Raw odor signals are transformed into refined patterns through lateral inhibition
• Lateral inhibition enhances contrast between odor representations, in which sharper odor discrimination can happen

Glomeruli Synapses

• Axons from olfactory receptor neurons (ORNs) synapse onto mitral and tufted cells (principal output neurons) in the glomeruli, found in the olfactory bulb
• Inhibitory interneurons—mainly periglomerular cells and granule cells—play a key role in lateral inhibition

Neural Activity Suppression

• Activity in neighboring neurons are suppressed as lateral inhibition happens when active neurons and contrast between odor representations increases

Periglomerular Cell Process

• Inhibition between neighboring glomeruli is supplied by Periglomerular cells
• Adjacent glomeruli are inhibited when a specific glomerulus is activated by an odor, reducing their response
• Sharpening odor selectivity happens when the most strongly activated glomeruli is emphasized

Feedback Synapses

• Granule cells form reciprocal synapses with mitral and tufted cells and the output neurons of the olfactory bulb
• Inhibitory feedback limits excessive firing and refines odor representation when a mitral cell is strongly activated
• Granule cells also helps improving contrast and reducing activity in nearby mitral cells as lateral inhibition is created which responds to similar odors

Multiple Cortical Areas

• Different aspects of odor perception, identification, memory, and emotional responses are contributed when olfactory information is processed in multiple cortical areas
• Olfactory signals bypass the thalamus and directly reach higher brain regions, allowing for rapid and complex processing unlike other sensory systems

Pathway Process

• Olfactory receptor neurons (ORNs) in the nasal epithelium detect odorants sending signals to the olfactory bulb
• The olfactory bulb processes and refines these signals before relaying them to the primary olfactory cortex

Piriform Cortex

• The temporal lobe is located in the primary olfactory cortex is the main center for odor identification and discrimination
• Neurons obtain direct input from the olfactory bulb, and form a distributed, associative network rather than a topographic map
• Even when presented in mixtures, odor identity is encoded and helps inrecognizing odors in the piriform cortex

Olfactory Tubercle

• Odor-guided behaviors and multisensory integration (linking smell to taste or touch) takes part in the reward and motivation-related odor processing

Amygdala Response

• Emotional and behavioral aspects of odor perception are the response
• Association of odors with fear, pleasure, or aversion (smelling smoke to triggers fear/ like triggers)
• Pheromone processing and social behaviors in animals have strong links

Entorhinal Cortex

• The entorhinal cortex serves as a gateway between the olfactory system and the hippocampus which is essential for odor-based memory formation
• Memories and emotions can be triggered strongly when smells reminds people of past memories and emotions

Orbitofrontal Cortex Integration

• The higher ordered process integrates olfactory information with taste, vision, and touch, contributing to flavor perception/ Plays a role in odor preference, decision-making, and conscious odor recognition
• OFC impairments include the the ability to distinguish or recognize odors

Parallel Processing

• Olfactory information is distributed across multiple regions in parallel and does not get processed in a linear, hierarchical fashion
• Different cortical areas specialize in odor identity, emotional significance, memory, and conscious perception ensuring rich and adaptive processing of smells

Nervous System Simplicity

• A simplified model can be use to study olfactory processing and behaviour
• C. elegans has only 302 neurons, with a well-mapped olfactory circuit consisting of a small number of sensory neurons
• Neurons in C. elegans directly regulate behavior without necessitating for complex cortical processing

Olfactory Processing

• There's different olfactory neurons in C. elegans that detect for different odors
• AWA and AWC detect attractive odors
• ASH and AWB detect repulsive odors
• There is multiple stages of olfactory signals that gets processed (olfactory bulb, cortex), so C. elegans makes behavioral decisions directly at the sensory neuron level

Beneficial Odors

• Downstream neurons that promote forward movement (chemotaxis toward the odor source) get stimulated with When Activated, AWC neurons detecting food-related odors

Harmful Odors

• Chemicals and noxious stimuli ASH neurons detect aversive chemicals and noxious stimuli, which leads an immediate escape response, as well as backward movement or turning away

Olfactory Circuitry Adaptation

• C. elegans can adapt to odor stimuli over time, modifying ON- and OFF-pathway activity based on past experiences
• OFF responses may be suppressed when odors and the food deprivation are paired repeatedly altering future odor-driven behaviors
• Mammals don't have direct circuitry but C.Elegans do

Engagement of ON- and OFF-Pathways

• In C. elegans sensory neurons get activated by Ordorant withdrawal and engage on and off pathways
• Its a ability to detect both stimulus onset and stimulus offset allowing the worm to exhibit adaptive behaviors in response to changing environmental cues

Flexibility

• The olfactory system in C. elegans encodes both odor presentation and odor removal, enabling some flexible responses
• Groups mediate responses from different sensory neurons
• ON-pathway neurons gets activated when an odorant appears/ OFF-pathway neurons being gets activated when an odorant disappears

Fluctuating Odor Gradients

• AWC neurons respond strongly to odor removal rather than its presence and this response is crucial for tracking fluctuating odor gradients in the environment
• Exploratory behavior/reorientation (searching) increases AWC

Attraction

• Movement direction towards the source is promoted with the presence of AWA neurons which are in charged attracting odorants
• Chemical concentrations detection and ON responses for water-soluble views happens ASEL and ASER neurons

Gradients and Avoidance

• C elegans uses ON and OFF signaling to track odors effectively, and detects harmful Environments from OFF sources help
• There is a risk for staying in unfavorable spot in low levels from prolonged time but they can adapt over time

Pathways and Interneurons

• Motor neurons get modulated and sensory neurons directly interact with Interneurons,
• Downstream has AIB interneurons which regulate reorientation movements,
• Forward movement and the AWA on pathway connects to Ali I interneurons

Efficient Representation Through Projection Neurons

• ORNs help transform input for more efficient representation of process in insects
• The signal of discrimination,the contrast are efficiency encoding higher region from ORNS to the brain

Equivalent to Mammary Olfactory

• Sends actions equivalent from the action potential side
• Organized map of odor

Representation

• Enhances and improves odor recognition with help each

Glower MLS process

• Signals are sharpened through the weaker redundant signals creating a contrast
• Temp. Patterns modulate the time releasing

Processing and Innate Repsonses

• The pns receive the refined odor in areas that lead to two brain regions the mushroom. Body (for learning and memory)and the lateral home (olfactory responses)

Mammalian vs Accessory Pathways

• Main and accessories olfactory pathways have learning and memory in it
• The accessory systems or detects pheromones/socials via

Projections to Amygdala

• A more stronger fast behavior responds related to mating are the results

Insect Systems and Rapid Bhevaiors

• Mating and reactions occur ( pheromones is and has to trigger these behaviors)

Memory/Learning

• A better rapid in a memory sense for better survival for detection vs to casting