In the previous article, we briefly discussed how cilia
allows a cell to move. In this article, we will focus on how cilia can also
function as a signal-receiving antenna.
Cells that need to be aware of their surroundings have a
non-motile cilia. Non-motile means not capable of movement. There can only be
one such cilium per cell. In vertebrate animals, almost all cells have such a
cilium, known as primary cilium. It has been implicated as a complex
signaling center for the cell, regulating key signaling pathways during
development. In fact, they are said to be highly sophisticated biological
sensors and have been under the focus of scientists in the past decades. As
this organelle can be found on all cell types, it’s importance extends to most
organ systems.
How does it transmit signals?
The membrane proteins of a primary cilium transmit molecular
signals from the cell's environment to its interior, initiating a signaling
pathway. It helps the cell to sense its surroundings. But what is a
signaling pathway? And how does the membrane transmit signals? Let’s understand
the structure of cilia to answer these questions.
Structure of cilia
The structure of this versatile extracellular sensor is
paramount to its functioning as defects in the primary cilium is linked to
pathologies such as arthritis, heart failure, obesity and cancer.
There are three types of cilia: motile, primary and nodal.
Non-motile cilia are also called primary as they develop
before the motile cilia in the central nervous system. The structure is quite
similar to the structure of motile cilia as it has nine microtubules arranged
in doublets, bound together in a membrane. But unlike a motile cilia, primary
cilia do not have a 9 + 2 arrangement (called 9+2 axoneme), meaning that they
don’t have 2 microtubules along the central axis. Hence, they have a 9 + 0 axonemal
structure. They also don’t have large motor proteins called dyneins which make
movement possible in cilia.
The primary cilium, on the other hand, senses and responds to fluid flow by bending, adding to its sensory capabilities. This shows how the molecular structure affects the function of the organelle.
In general, cilia is said to be made up of compartments: 1)
membrane domain: it is made up of proteins and lipids different from the plasma
membrane. It is specialized to support sensitivity as it has many sensory
receptors and channels. 2) the soluble component: it also known as the matrix component
or cilioplasm. It consists of a fluid material between axoneme (the tubular
structure) and ciliary membrane. This is where the intraflagellar transport
(IFT) system, a highly conserved mechanism, assembles and maintains the cilia
after growth arrest. 3) axoneme: a tubulin-based structure that allows motor
proteins to transport ciliary components to the cilia. 4) tip : distal part of
cilia. The function of it is unknown as it is said to contain more than 1000
types of proteins. The protein complexes have specialized functions.
A detailed look on how a cilia senses its surroundings
How it senses changes in extracellular fluid flow?
Cilia responds to changes in fluid flow, which causes fluid
shear stress, by bending. This process is known as mechanosensing.
Cilia is made up of polycystin-1 and polycystin-2 proteins
which serve as a mechanosensor complex. Polycystin-2 serves as a calcium
channel and requires polycystin-1 to mediate an intracellular calcium
mobilization. The mobilization of ions is how cilia communicates changes in
external fluid flow.
The mechanosensory functions of polycystins and primary
cilia have been studied in various tissues of the human body. Primary cilia
from other systems, such as endothelial cells isolated from embryonic mouse
aorta, respond to fluid shear stress, similar to blood flow, by inducing an
increase in intracellular calcium mobilization.
Primary cilia play an important role in transducing extracellular
signals such as fluid shear stress into intracellular biochemical
responses such as calcium signalling and nitric oxide synthesis.
Polycystin-2 is found in human and mouse endothelial cells and is required to
sense fluid shear stress. It was proposed that ciliary polycystin-2 is a shear
sensitive calcium channel required to activate a biochemical cascade which
involves calcium, calmodulin, Akt/PKB and protein kinase C and leads to the
synthesis of NO. The nitric oxide production controls vascular tone and systemic
blood pressure.
·
Vascular tone refers to the contractile activity
of vascular smooth cells in the walls of small arteries and arterioles. It is a
major determinant of resistance to blood flow through circulation.
·
Systemic blood pressure is the pressure
measured by large arteries in the systemic circulation of blood.
From the information about changes
in fluid flow through cilia, the cell responds by controlling the resistance to
blood flow and blood pressure. Hence, a feedback loop is formed.
Role in olfactory signaling
Olfactory refers to smell. In this section, we would be
studying how primary cilia senses smell. Olfactory ligands (chemical compounds)
bind to the olfactory receptors on
the ciliary membrane of olfactory sensory neurons. This leads to the
olfactory signaling cascade through the production of the second messenger
Cyclic Adenosine Monophosphate (cAMP) within the cilium. This leads to the
depolarization of the cell by the opening of the cyclic nucleotide gated
channel located in the cilia.
·
Cyclic nucleotide gated channel is an ion
channel activated by the binding of cAMP. Channels are important cellular
switches which transduce changes in intracellular concentrations of cyclic
nucleotides into changes of the membrane potential and the Ca2+ ion
concentration.
·
Cyclic nucleotides are intracellular second
messengers that regulate cell function by controlling the activity of
protein kinases which in turn control other proteins.
·
Second messengers are intracellular
signalling molecules released by the cell in response to extracellular signalling
molecules- the first messengers. They can cause depolarization.
·
Membrane potential is the difference in
electric potential between the interior and exterior of a biological cell.
The binding of olfactory ligands allows the opening of cyclic
nucleotide gated channel which depolarizes the cell through changes in concentration
of calcium ion and membrane potential. Through this process, it transmits information.
Hence, neurons lacking cilia lack the ability to sense odour.
Role in photo receptor signaling
Photo refers to light. The sensation of light is mediated
through the photoreceptors in retina, known as cone and rod cells. The cilium
in such cells is characterized by a specialized tip called outer segment where
the photo receptors that receive and initiate the reception of light are
localized. The signal is initiated by the increase in cyclic guanosine
monophosphate (cGMP) which soon causes the closure of cGMP channel. Maintenance
of this signaling cascade requires the transport of retinal proteins called
Rhodopsin through the intraflagellar transport system (IFT). Rhodopsin, a visual pigment
found in the rod photoreceptor cells of the retina, is responsible for converting
photons into chemical signals that stimulate biological processes in the
nervous systems of humans and other vertebrate animals, allowing them to sense
light.
Conclusion:
In nature, even a miniscule organelle, when involved in a system,
can have prominent effects on an organism as a whole. Such knowledge is encouraging
for anyone who wants to dive deeper into the study of biology. Happy learning!
Bonus knowledge: The role of cilia in cancer
Multiple genes cause the same ciliopathy (diseases caused by
defects in cilia) and mutations in the same gene can result in different
ciliopathies in different individuals. But as most proteins found in cilia are
found at other cellular sites as well, it is difficult to attribute a phenotype
to defective cilia.
The primary cilia garnered most interest when it was linked
to the sonic hedgehog pathway (shh), which is a critical developmental pathway,
unregulated in cancer. SHH pathway is defined as a pathway that signals through
the primary cilium. The proteins involved in ciliogenesis (formation of primary
cilia) are overexpressed in some cancers. They are the proteins associated with
assembly/maintenance of cilia. It can be inferred that as the microtubules in
cilia are also involved in mitosis (they separate the duplicate chromosomes),
overexpression of cilia proteins could lead to increase in cell division, resulting
in cancer.
References:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1382026/
https://www.sciencedirect.com/topics/neuroscience/cyclic-nucleotide