Sensing Time and Chemicals

Endogenous rhythms

• regular and cyclical variations of function

• not dependent on incoming sensory information

BUT→ can be modulated by sensory information

Advantage of endogenous rhythms

• predictive of regular environmental changes

Three major rhythms

• circannual→ seasonal reproduction, migration, fat accumulation, dormncy

• cicadian→ one a day

• circatidal→ 12.4h half a lunar day for marine creature

What are circadian clocks

• endogenous 24 hour rhythm

• anticipate light levels

• match activities to the day/night cycle

Where found?

• Ubiquitous

• in plants, animals and bacteria

How do they compare to homeostatic feedback control?

• exert feed-forward control over effectors

What do they control

• sleep/wake cycle

• feeding

• excretion

• temperature

• diuresis

• blood pressure

What happens if they are left to free run?

• become desynchronised

  • why: intrinsic rhythm is not exactly 24 hours

• THEREFORE: need to maintain circadian clock ticking by entrainment

How does the ryhtm entrained?

• Not with rods or cones

• new photoreceptor: intriniscally photosensitive retinal ganglion cells ipRGCs

• contain melaopsin

  • different kind of opsin

found in the retina

Melanopsin

• most closely related to insect r-opsins

• than to c-opsins in rods and coes

How does Melanopsin act

• Through PLC and TRP channels

• Use G-protein signalling cascade

• Similar to Drosophila photoreceptors

Where is the master clock in the mammalina brain

• Suprchiasmatic nucleus (SCN)

• of the hypothalamus

How is this rhyhm made

• intrinsic rhythm of electrical activity

• around 25 hours

• entrained by neural signals from the retina

• → to make it precise 24 hour neural clock

• Drives cyclic changes

  • hormone secretion

  • sleepiness

How does the clock also deduce the time of year

• relative lengths of day and night

→ kind of similar to that in plants!

Why can’t a neural circuit generate the rhythem?

• Action potentioals and synaptic events would seem too fast to underlie a slow 24hr cycle

Instead, for the clock you need…

• slow cycle of gene expression

• and protein synthesis

→ just as in plants

What is the molecular clock

• slow build-up of “clock protein”

• Clock proteins have a short lifespan

• require the acitivity of transciption factors→ e.g CREB (c-AMP response-element binding protein) to be synthestized

• When present, the clocl protein acts on the trasncitption factors themselves→ inhibiting them and therefore stopping own production

(summaried next!)

Cascade of the olecular clock

1. CREB transciption facotr initiates produciton of clock proteins

2. clock protein inhibit CREB (negative feedback)

3. Production of clock protein stops

4. Previously made clock protein degrade

5. inhibition of CREB is lifted

6. Trasnciption of clock genes resumes, clock proteins are made, the cycle starts again

If it was let to free run…

• cycle would take 25 hours

→ input of ipRGCs are needed

ipRBC input

1. activates metabotropic receprots

2. via second messengers and kinase

3. Activate CREB

4. locking the cycle to the actual day-night cycle

Plant vs Animal clocks

Plants:

• autonomous in the plant cell

• each cell has its own circadian clock

• respons directly to light

Animals

• in the SCN→ although small animals are more cell-autonomous

Taste and smell in vertebrates vs invertebrates

Vertebrates

• Metabotropic receptors mainly

Invertebrates

• largely due to direct ionotropic mechanisms

How is transduction initiated in both of these?

1. physical binding of the chemical molecule

2. To xbspecific receptor

→ similar to neurotransmitter to postysnaptic receptors

What makes chemical sensing hard to do?

• Chemical space is immense

  → Difficult to convery so much information with a limited set of receptors

Gustation

• chemical sense that requires physical contact

• with source for detection

Olfaction

• chemical sense that detect chemicals emanating from a distant source

What functions does taste have?

1. aversive→ avoid toxic stuff

2. Attractant→ get nutrition etc

5 distinct taste sub-modalities

1. sweet

2. umami

3. bitter

4. sour

5. salt

→ each with its own receptor proteins→ taste receptor cells and transduction mechanism

Features of taste receptor cells

• short receptors

• localised in taste buds

• in papillae on the tongue and palate

Tasting for good

• sweet

• umami

Tasting for bad

• bitter

• sour

• salt

Salt attractive or aversive?

• Both

Taste is also strongly informed by

• olfaction

Ionotropic taste receptors

• salt

• sour

How taste salt

1. Na+ ions flowing into sensory cell

2. depolarising it

3. constinutitecely open Na+ channel

Salt at low levels

We like:

1. Mediated by Na+ ions floing through epithellal ionotropic channel

Salt at high concentrations

1. Uses receptor channel protein for aversive salt

2. not known

3. expressed in different cells from those that detect low salt

HOw taste sour

1. undissociated (uncharged) weak organic acids

2. diffuse freely through the cell membrane

3. become ionised within the cytoplasm

4. releasing protons which modulate activity of pH-sensitive ion channels form inside the cell

Weird thing about strong acids?

1. Do not easily cross the membrane

2. don’t taste as sour!

Metabotropic taste receptors

1. Sweet

2. Umami

3. bitter

Types of receptors used

• All GPCR

• share common metabotropic G-protein signalling cascade

How work?

1. The GPCRs act via another specific G-protein (gustducin)

2. Actiavtes a phospholipase C enzyme

3. eventually results in Na+ entry and repolarisation

No. of GPCRs for ‘nice’ vs ‘bitter’

• 2 for nice→ repond to very high concentrations

• 25 for bitter→ respond to low concentrations→ small amount might be lethal

As all 25 bitter receptors are expressed in the same cell

• we can’t use them to distinguish different bitter tastes

Chemosensation in plants

• Can detect leaf volatiles in response to chemicals secreted

  • e.g aphids or insect eggs

• Other plants can sense eaf volatiles→ prepare themselve to resist attack

  • e.g producing toxins

Features of receprot cells for taste and asmall in insects

• long receptors

• sensory endings embedded in sensory bristles (sensilla)

What happens when volatile odaours/tastants reac the surface of the recpor

1. reach by diffusing through microscopic pores in the tip or walls of the bristles

2. Follow the direct ionotropic principle

GCPR in insects?

1. taste and olfactory resemble GPCR→ they have 7 transmembrane domains

BUT

• no homology to vertebrate

Drosophila OR genes in olfactory sensilla

1 family of 50 genes:

• expressed in antennae and maxillary palps

2nd family of 60 genes

• related to ionotropic glutamtate receptors

• presumed to be ionotropigc glutamtate receptos

• ionotropic, ligand-gated ion channels

Where are taste receptors expressed in the Drosophila

• In the sensilla:

  • mouthparts→ proboscis

  • legs

  • wings

  • gentitalia

→ good before you put it in yur mouth

Similariy to taste buds

• one chemosensory sensillum has a range of chemorecpetor cells

• e.g

  • sensitive to salt and water

  • mechanosensory neuron

Type of recepors that are taste receptors

• also believed to be ionotropic

• forming cation channels direclty gated by sugars or bitter compounds

Where is the olfactory epithelium is vertebrates

• high in the nasal cavity

• contains arounf 5 million olfactory receptors

Strucutre of the olfactory epithelium

1. cillila

2. lies in layer of mucus

3. in contact withthe air

4. axon arise from the cell ody and passes through perfoation in the base of the skull to rach the olfactory bulbs in the brain

THEREFORE→ olfactory recepors cells are long receptors

one expressed per cell!

What happens when they die?

• repeatedly replaced

• thorughout lifetime from quiescnet stem cells

How connected differently to the brain than photoreceptors?

• main basic connective it to the limbic sysem

• does not pass the thalamas

  • fast at evoking emotions and memories

How to smell?

1. air-borne volatile odorant molecules dissolve in the mucus

2. bind to receptor proteins in the cillia and recepto cells

3. 350 different odorant receptor proteins

Type of receptor proteins?

• all GPCRs

• encoded by different gene

• helping to make the GPCR family the largest gene family in our genomes

Olfactory transduction

1. GPCR activated G-protein Golf within the cilia membrane

2. single activated GPCR molecule may activate more than one G-protein→ AMPLIFICATION 1

3. each alpha subunit activates one adenyl cyclase→ synthesises more molecules of cAMP AMPLIFICATION 2

4. cAMP activates cyclic nucleotride-gasted (CNG) channels

5. open to allow the entry of Na+ and Ca2+→ leading to depolarisation

6. initiate action potential in the axon

7. Phosphodiesterase PEDE degrades the c-AMP to AMP→ to end the sensory response

Apart from receptor potential depolarisation, the Ca2+ also

Is a second messenger:

1. Ca2+ binds to Cl= channels

2. open to allow Cl- efflus

   →unusual efflux negatively charged Cl- enhances the depolasiration

Also leads to adaptation→ similar to photoreceptors!

• Ca2+ enters via channels→ leads to adaptation

• modulating the activity of different steps in the transduction cascade

Why does this occur

• occurs because a secondary active trasnport system (NaCCK cotransporter)

• makes the Cl- concentration within the cilila particulalrly high

1. occurs because a secondary active trasnport system (NaCCK cotransporter) makes the Cl- concentration within the cilila particulalrly high

Compare & contrast:

note the similarities and differences with phototransduction – the main differences being that cAMP is used rather than cGMP and that the Golf activates a cyclase rather than PDE, so that CNG channels open instead of closing.

How can a few receeptors in the olfactory epithelium encode for millions of chemicals present in the environment?

• each receptor cell expresses copies of only one of those receptor proteins

• all receptor cells expressing the same odorant receptor protein project the same glomerulus in the olfactory bulb

• A given receptor protein might bind specificically to a small subset of odorants

What happens when an odorant bind to several different receptor proteins with different ‘sides’ of the molecule

1. a given chemical or mix of chemicals might stimulate a unique subset of 350 different receptor proteins/cells/ gloermuli

2. forms the basis of a powerful ‘combinatorial code’

3. Allows humans to dicriminante at least millions of olfactory stimuli

Pheromones to the olfactory system?

No, different to the the detection of colatile chemicals

• sense with vomero-nasal organ (VNO) near the regular olfactory mucosa

What does the vomero-nasal organ do

1. sends info to the accessory olfactory bulb (AOB)

2. creating parallel system to the olfactory epithelium (main olfactory bulb)

3. Controls innate behaviours such as mating, parenting and fighting

What are the receptors in the VNO

GPCR odorant receptors

1. VRs→ vomeronal receptors, detect pheromones

2. TAARs (Trace amine-associated receptors)→ detect proteinaceous prey/predator chemical cues

Aimilar transduction but ultimately target different areas in the the brain

Humans use pheromones?

• mice have 150 pheromone detecting VR genes

• HUmans→ only 10→ most are non-functional pseudogenes

• vestigial VNO at best