Lectures 10, 11 and Paper 1

Rachel A. Kaplan and Elbert Heng3.11.14

Announcements

• You have an exam next week, get amped• Spring break is after your exam next week,

also become accordingly amped• You should have read Paper 1 for today’s

section• It’s my birthday one month from last Sunday,

so if you want to get me a present…

LECTURE 10: INDIRECT MECHANISMS OF SYNAPTIC TRANSMISSION

LECTURE 11: MECHANOSENSATION

Mechanosensation

• Definition: detection of physical movement (of things around, in and on your body)– e.g. touch, stretch, pressure, sound , movement

Accomplished by mechanosensory neurons

• Stretch-gated channels tethered to intra and extracellular matrices– Fast, sensitive, adaptable (so that it can transduce a

wide range of inputs), and specialized• Lots of receptor subtypes– E.g. Pacinian Corpuscles

• Respond to vibration because they are fast adapting• Neuron is surrounded by epithelial cells that form many

layers of gelatinous membranes called lamellae– Pressure on causes neurons to fire– Pressure off also causes neurons to fire

C. Elegans is a model

• It responds to gentle touch on its neurons– ALM, PLM, AVM, PVM– Neuron’s response: inward Na+ current to touch

immediately• Therefore it is putatively a mechanosensitive neuron

• Mec-4 is a gene that when mutated eliminates stretch currents (and therefore touch sensitivity)

• Mec-10 mutation causes channel to be leaky and causes toxic gain of function– Both Mec-4,10 are channel subunit proteins

More Neurons/Proteins Involved

• Degenerin/ENaC Channels– Respond to stretch/mechanical stimulation – slow

adapting• CEP Neurons – Senses viscosity of surrounding bacteria– Rapidly adapting cation channel– TRP-4: mechanosensory channel

• Other TRP Channels– Sense temperature, chemical tastants

Hearing and Proprioception

• Vibrations of air are transduced by mechanosensory hair cells – Stereocilia are deflected, links between stereocilia are

stretched, allows K+ inward current to depolarize cell• Deflecting the other way will hyperpolarize the hair cell• Stereocilia adapt by tightening tip links

• Movement of head in space is transduced by similar hair cells in other organs – Utricle and sacculus – linear acceleration moves gel and

crystals, causes opening of hair cells – Semicircular canals – rotational motion causes fluid in canals to

move ampulla and embedded hair cells

More on hearing…

• Basilar membrane moves hair cells against tectorial membrane, that moves stereocilia

• Outer hair cells tension the tectorial membrane - amplify vibrations– OHC depolarized by movement, their

depolarization makes them change their size, them changing their size moves the tectorial membrane which causes more depolarization in OHC and IHC

PAPER 1: GLUTAMATE-MEDIATED EXTRASYNAPTIC INHIBITION: DIRECT COUPLING OF NMDA RECEPTORSTO CA 2+-ACTIVATED K+ CHANNELS

In a nutshell…Putative K+ Outward Current from BK Channels

Putative Ca2+ and Na+ Inward Current from NMDARs

This is necessary

for this

Introduction

• NMDARs are Glutamate Receptors– Causes Ca2+ and Na+ influx– Mg2+ block membrane when hyperpolarized – Ca2+ is a 2nd messenger and is crucial for plasticity

(LTP, LTD)• BK Channels are Ca2+ Activated Channels– Causes K+ efflux which hyperpolarizes membrane– Alters neuronal excitability

Hypothesis

• Ca2++ influx from NMDAR activation in turn activates BK channels, which makes it more difficult to depolarize the cell, affecting neuronal excitability. – A new function for NMDARs!

Figure 1 A1, A2

Figure 1B, 1C (not shown)

NMDAR Block K+ Block

Figure 1D

Additional Experiment Between Figures…

• Glu generated largest inhibitory currents when applied to soma but no inhibitory currents when applied to dendrites!– Conclusion: this special phenomenon of NMDAR

mediated outward current is localized

Fig 2A, 2B

Figure 3

Step current (outward)

NMDAR mediated current (outward)

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8A

hyperpolarization

depolarization

Figure 8B